Ureidoacetamido-penicillins

ABSTRACT

6-(α-3-Acyl-ureidoacetamido)-penicillanic acids and pharmaceutically acceptable non-toxic salts thereof in which the hydrogen atom of the nitrogen atom present in the 3-position is substituted, are effective against Gram-positive and Gram-negative infections, particularly Klebsiella aerobacter infections.

CROSS-REFERENCE

This is a divisional of our copending applications Ser. Nos. 145,809 and145,877 filed May 21, 1971, now abandoned.

The present invention relates to new penicillins which are useful asanti-bacterial agents for humans, poultry and animals, and foodstuffadditives in animal fodder. They are particularly useful in thetreatment of illnesses due to infection by Gram-positive andGram-negative bacteria, and especially by Klebsiella bacteria such asKlebsiella aerobacter.

Anti-bacterial agents, such as ampicillin (U.S. Pat. No. 2,985,648) haveproved very effective in the therapy of infections by Gram-positive andGram-negative bacteria. However, they are not capable of effectivelycombating Klebsiella infections. Carbenicillin U.S. Pat. Nos. 3,142,673and 3,282,926) is only effective in man in the case of infections byKlebsiella bacteria if it is administered in continuing high doses, suchas are only achieved by infusion.

6-(α-3-Acylureidoacetamido)-penicillanic acids are described inNetherlands Pat. Nos. 69,01646 and 69,08909 and in U.S. Pat. Nos.3,479,339, 3,483,188 and 3,481,922 and German Offenlegungsschrift1,959,920 but all 3-acylureido acetamidopenicillanic acids described andclaimed in these Patents posssess, in contrast to those of the presentinvention, a hydrogen atom on the nitrogen atom present in the3-position in the acylureido group. The presence of this hydrogen atomand the absence of anoher substituent at this position of the acylureidogroup in part necessarily results from the different way of synthesisingthese penicillins.

More particularly, the present invention is concerned with penicillinsof the formula: ##EQU1## or a pharmaceutically acceptable non-toxic saltthereof wherein

A is a group of the formula: ##EQU2## wherein X is hydrogen, alkyl,preferably lower alkyl, alkenyl, preferably lower alkenyl, cycloalkyl orcycloalkenyl with up to 10 carbon atoms, arylvinyl, especiallyphenylvinyl, mono-, di-, or tri-halo(lower alkyl), (lower alkyl)amino,di(loweralkyl)amino, monarylamino, aryl especially phenyl (loweralkyl)amino, aryloxy especially phenoxy, alkoxy or aralkoxy with up to 8carbon atoms, cycloalkoxy with up to 7 carbon atoms, or a group of theformula:

(lower alkyl)-O-V- (5);

(lower alkyl)-S-V- (6);

N.tbd.c-v- (7);

(lower alkyl)-O-CO-V- (8);

di(lower alkyl)amino-CO-V- (9); ##SPC1##

wherein

V is a bivalent organic radical with 1 to 3 carbon atoms;

n is 0, 1 or 2;

R₁, r₂ and R₃ are the same or different and are each hydrogen, chlorine,bromine, iodine, fluorine, nitro, cyano, di(lower alkyl)amino, di(loweralkyl)aminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, loweralkanoyloxy, lower alkyl, lower alkoxy, sulphamyl or trifluoromethyl;

Y is alkyl, especially lower alkyl, alkenyl, especially lower alkenylsuch as vinyl and propenyl, cycloalkyl or cycloalkenyl with up to 10carbon atoms, mono-, di-, or tri-halo(lower alkyl), aryl especiallyphenyl, a heterocyclic group, or aralkyl with up to 8 carbon atoms;

--Z-- is a divalent group of the formula:- ##EQU3## wherein m is 3, 4 or5 and the arrow means that the two free valencies of the group Z are notarbitrarily joined to the N and C atoms of the group ##EQU4## but areoriented as indicated by the arrow; Q is a divalent group, and inparticular a group of the formula: ##EQU5## ##SPC2##E is oxygen orsulphur; G is hydrogen or lower alkyl; R₁ and R₂ are as above defined;the arrow in the divalent group Q means that the two free valencies ofthe group Q are not arbitrarily joined to the two nitrogen atoms of thegroup but are oriented as indicated by the arrow: M is a group of theformula: wherein

E and G are as above defined; B is a group of the formula: ##SPC3##

wherein

R₄, r₅ and R₆ are the same or different, and are each hydrogen, halogen,lower alkyl, lower alkoxy, lower alkylthio, lower alkylthionyl, loweralkylsulphonyl, nitro, di(lower alkyl)amino, lower alkanoylamino,hydroxy, or lower alkanoyloxy and which, as regards the chirality centerC, can have either of the two possible R- and S- stereomericconfigurations.

The invention covers not only pure R- and S-stereoisomers, but alsomixtures of these isomers in any proportions.

The salts to which the invention more particularly relates are thenon-toxic pharmaceutially tolerated salts, which include salts of theacid carboxyl group.

The above mentioned pharmaceutically acceptable non-toxic toleratedsalts include salts of the acid carboxyl group, such as sodium,potassium, magnesium, calcium, aluminium and ammonium salts, andnon-toxic substituted ammonium salts with amines such as di- andtri-lower alkylamines, procaine, dibenzylamine,N,N'-dibenzylethylenediamine, N-benzyl-β-phenylethylamine,N-methylmorpholine and N-ethylmorpholine, 1-ephenamine,dehydroabietylamine, N,N'-bis-dehydroabietylethylenediamine, N-loweralkylpiperidine and other amines which have been used for formng saltsof penicillins.

The term "lower alkyl" is to be understood, in the present invention, asmeaning both a straight-chain and a branched alkyl group with up to 6carbon atoms. In conjunction with other groups, such as in "di-loweralkylamino," the term "-lower alkyl-" only relates to the alkyl part ofthe particular group.

The phrase "the compound of the present invention" includes thepharmaceutically acceptable non-toxic salts of the penicillins of thepresent invention.

According to one embodiment of the present invention A is: ##EQU6## B isphenyl.

These steroisomers in which the chirality center *C is in theR-configuration, i.e. D(-)-, are preferred.

According to another embodiment of the present invention:

B is p-methylthiophenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenylor thienyl-(2).

According to another embodiment of the present invention:

A is pyrrolid-2-on-1-yl;

B is phenyl or tolyl; and

*C can have either of the two possible R-- and S-- steroisomericconfigurations or it can be a mixture of such diastereomers.

The preferred salt is the sodium salt and particularly preferred sodiumsalts are those wherein *C has the D(-)- configuration.

The invention further provides a process for the preparation of theabove penicillins and salts in which 6-aminopenicillanic acid (52) or acompound of the formula (53) or (54): ##EQU7## in which R₇, R₈ and R₉are the same or different alkyl having up to 6 carbon atoms;

is reacted at a temperature of -30 to +50°C with a carboxylic acid ofthe formula: ##EQU8## modified at the carboxyl group, wherein A, B and*C are as above defined.

This reaction is, when 6-aminopenicillanic acid is used, carried out inan anhydrous or aqueous solvent, in the presence of a base. If acompound of the formula (53) or (54) is used, the reaction is carriedout in an anhydrous solvent, free of hydroxyl groups, with or withoutthe addition of a base.

The carboxyl group of the carboxylic acids of the formula (55) may bemodified by either

(i) reacting such a carboxylic acid with about one molar equivalent of acompound of the formula (56), (50), (51), or (52): ##EQU9## wherein R₉is as above defined;

R₁₀ is the same as R₉ and in addition may be phenyl;

R₁₁ is a divalent organic radical (CH₂)₄, CH₂)₅ or (CH₂)₂ O (CH₂)₂ ; and

W is halogen;

in an anhydrous, inert organic solvent in the presence of about onemolar equivalent of a base at a temperature of about -60°C to +30°C; or

ii. by converting a carboxylic acid of the formula (55) into thecorresponding carboxylic acid derivative of the formula (60): ##EQU10##wherein A, B and *C are as above defined and each U is --CN or --COO--lower alkyl.

The carboxylic acid derivatives of the formula (60) may be prepared byreacting a compound of the formula (61): ##EQU11## wherein U is as abovedefined,

in an anhydrous, inert organic solvent, in the presence of at least onemolar equivalent of a tertiary organic base, at a temperature of from-25°C to +25°C, with one molar equivalent of thionyl chloride, to obtainan intermediate product, with one molar equivalent of base hydrochloridebeing formed. The intermediate product is then reacted, withoutisolation and in the presence of a further molar equivalent of a base,with a molar equivalent of the carboxylic acid of the formula (55) at atemperature of about -25°C to +25°C, to give the modified carboxylicacid of the formula (60).

In carrying out the process of the invention using 6-amino-penicillanicacid, the modified carboxylic acid of formula (55), preferably in theform of a solution in an anhydrous, inert organic solvent, is broughttogether with a solution of 6-aminopenicillanic acid in water or in anaqueous or anhydrous organic solvent, in the presence of a base.Suitable solvents for the carboxylic acids modified at the carboxylgroup are, for example, acetone, tetrahydrofurane, dioxane,dimethylformamide, dimethylsulphoxide and hexamethylphosphoric acidtriamide for an aqueous reaction medium, and preferably methylenechloride and chloroform for an anhydrous reaction medium.

The 6-aminopenicillanic acid is preferably employed in the reactionaccording to the invention as a solution of its salt with a base, inwater or in a mixture of water and a water-miscible solvent, or in ananhydrous organic solvent. Suitable solvents for the 6-aminopenicillanicacid or its salt, apart from water, are preferably acetone,tetrahydrofurane, dioxane, acetonitrile, dimethylformamide,dimethylsulphoxide, hexamethylphosphoric acid triamide and isopropanolfor an aqueous medium and, in addition to the solvents mentioned,preferably methylene chloride and chloroform for an anhydrous reactionmedium. In ordfer to convert the 6-aminopenicillanic acid into the saltof a base, the salt being dissolved in a solvent, inorganic bases suchas sodium carbonate, sodium hydroxide, sodium bicarbonate, thecorresponding potassium and calcium compounds, magnesium oxide ormagnesium carbonate or buffer mixtures can for example be used as basessuitable for the purpose in the case of an aqueous or water-containingreaction mixture, whilst triethylamine, pyridine, diethylamine,N-ethylpiperidine or N-ethylmorpholine can preferably be used in thecase of an anhydrous reaction medium.

The reaction, according to the invention, of the carboxylic acids of theformula (55), modified at the carboxyl group, with the silylated6-aminopenicillanic acids of the formulae (53) and (54) is carried outin inert organic solvents which are free of hydroxyl groups, for examplein carbon tetrachloride, methylene chloride, chloroform,tetrahydrofurane, benzene, diethyl ether and toluene.

The reaction, according to the invention, of the carboxylic acids of theformula (55), in the form which is modified at the carboxyl group, withthe 6-aminopenicillanic acid, in an aqueous or water-containing medium,can be carried out at a pH of, preferably, 6.5 to 8.0, or also at a pHof about 3.

As in the case of most chemical reactions, higher or lower temperaturesthan those indicated in the Examples can be used. However, if the valuesindicated in the Examples are substantially exceeded, side-reactionswill occur to an increasing extent, and these reduce the yield ordisadvantageously affect the purity of the products. On the other hand,excessively lowered reaction temperatures reduce the speed of reactionso much that reductions in yield can occur. Reaction temperatures of-20°C to +30°C are therefore preferred in the reaction according to theinvention, of the carboxylic acids of the formula (55), modified at thecarboxyl group, with the 6-animopenicillanic acid or the silylated6-aminopenicillanic acids of the formulae (53) and (54). Only in caseswhere the carboxylic acids modified at the carboxyl group areinsufficiently stable, or there is the danger that racemisation mayoccur at an optically active centre located near the carboxyl group, canit be advisable preferably to carry out the process at reactiontemperatures below -20°. In the reaction, according to the invention, ofthe carboxylic acids of the formula (55), modified at the carboxylgroup, with the 6-animopenicillanic acid or the compounds of theformulae (53) and (54), the reactants can be reacted in equimolaramounts. It may however be advisable to use one of the two reactants inexcess in order to facilitate the purification of the desiredpenicillin, or its preparation in a pure form, and to increase theyield. Thus it is, for example, possible to employ the6-aminopenicillanic acid or the compounds of the formulae (53) and (54)in an excess of 0.1 to about 0.4 mol equivalent and thereby to achievebetter utilisation of the carboxylic acids of the general formula (55).When working up the reaction mixture and isolating the penicillin,6-aminopenicillanic acid which may be present can be easily removedbecause of its good solubility in aqueous mineral acids. Any carboxylicacid [see formula (55)] which may be present can, on the other hand,only be separated with much greater difficulty from the penicillinformed.

The amount of bases added in the reaction, according to the invention,of the carboxylic acids of the formula (55), modified at the carboxylgroup, with 6-aminopenicillanic acid or the compounds of the formulae(53) and (54) is for example determined by the desired maintenance of aparticular pH. Where a pH measurement and adjustment is not carried out,or is not possible or sensible because of the absence of sufficientamounts of water in the diluent, about 0.5 to 2.0 mol equivalents ofbase are added in the case where he compounds of the formula (53) or(54) are used, and about 1.5 to 2.5 mol equivalents of base are added inthe case where 6-aminopenicillanic acid and an anhydrous reaction mediumare used.

The working up of the reaction batches for the manufacture of thepenicillins according to the invention, and of their salts, in all casestakes place in the manner generally known for penicillins.

The carboxylic acids of the formula (55) can be modified at the carboxylgroup, according to the invention, by reacting them with about one molarequivalent of a compound of one of the formulae (56), (57), (58) or (59)in an anhydrous, inert organic solvent in the presence of about onemolar equivalent of a base, preferably a tertiary organic base, at atemperature of about -60°C to +30°C, preferably -30°C to +5°C, mostpreferably -20°C to +5°C. The forms of the carboxylic acids, modified atthe carboxyl group, which are thereby produced are preferably notisolated, but used, together with the solvent in which they are present,for the reaction with the 6-aminopenicillanic acid or the compounds ofthe formulae (53) or (54). If the reaction mixture for the reaction withthe aminopenicillanic acid contains water, organic solvents which aremiscible with water, for example acetone, tetrahydrofurane, dioxane,dimethylformamide, dimethylsulphoxide or hexamethylphosphoric acidtriamide, are preferentially used as solvents for the reaction of thecarboxylic acids (55) with the compounds (56), (57), (58) or (59). Ifthe reaction mixture for the reaction with 6-aminopenicillanic acid doesnot contain any water, or if the reaction mixture for the reaction withcompounds of the formulae (53) or (54 ) is concerned, solvents such as,preferably, methylene chloride or chloroform are also used, in additionto the solvents mentioned.

According to the invention it is also possible to modify the carboxylicacids of formula (55) at the carboxyl group by conversion into thederivatives of the formula: ##EQU12## wherein A, B, *C and U are asabove defined.

This is expediently done by first converting a compound of the formula(61): ##EQU13## wherein U is as above defined,

in an anhydrous, inert organic solvent, for example acetone,tetrahydrofurane, methylene chloride, dioxane, chloroform ordimethylformamide, in the presence of at least, and preferably, one molequivalent of a tertiary base, preferably triethylamine, at temperaturesof about -25°C to +25°C, preferably -10°C, into an intermediate productby means of one mol equivalent of thionyl chloride, with one molequivalent of base hydrochloride being formed. This intermediateproduct, the constitution of which is unknown, is not isolated, but isreacted in the presence of a further molar equivalent of an organicbase, also preferably triethylamine, with one molar eqivalent of thecarboxylic acid of formula (55) at a temperature of about -25°C to+25°C, preferably -10°C to +10°C. After the base hydrochloride has beenremoved by filtration, the appropriate compound of the formula (60) canbe isolated by evaporating off the solvent and can optionally bepurified by recrystallisation from inert solvents or, if the substanceis not crystalline, by brief washing of a solution, for example in etheror benzene, with an aqueous bicarbonate solution at as low a temperatureas possible.

The 6-aminopenicillanic acid used as starting material in the process ofthe invention can be obtained by known methods, for instance by fissionof penicillin-G, either by microbiological or by chemical means (compareNetherlands Pat. No. 67/13809).

The carboxylic acids of formula (55) can be obtained from theamino-acids of the formula: ##EQU14## wherein B is as above defined,

by reaction with a compound of the formula:

    A -- CO -- W                                               (63)

wherein

A and W are as above defined.

The compounds of the formula (63) in which W is halogen, can be obtainedby processes described in German Offenlegungsschrift No. 1 793 287, inGerman Pat. No. 1,259,871, in U.S. Pat. Nos. 3,275,618 and 3,337,621,and in Japanese Pat. No. 434 247. Furthermore, some of the compounds offormula (63) in which W is halogen can be obtained from thecorresponding amide by metallization at the amide nitrogen atom withmethyl, lithium, followed by reaction with phosgene.

The compounds of formula (63) in which W is halogen and A is ##EQU15##

can be obtained from the cyclic ureas of formula:- ##EQU16## wherein Qis as above defined, and phosgene.

The reaction is illustrated in the examples.

The production of the reagents of the formulae (56), (57) and (59) isdescribed in the literature [see J. Med. Chem. 9, (1966), p980; Ber. 96,(1963) p2681; Tetrahedron 17, (1962), p114]. The reagent of formula (58)can be obtained from N,N'dimethylethylene diamine after converting itinto the N,N'-bis-trimethylsilyl compound, reacting this with phosgeneto give the corresponding cyclic urea, and reacting the latter withphosgene.

The penicillins according to the invention can also be obtained from thecarboxylic acids of the formula (55) and 6-aminopenicillanic acid, orthe silylated 6-aminopenicillanic acids [see formulae (53) and (54)] bythe known methods of peptide chemistry (see E. Schroder & K. Lubke, "ThePeptides," Methods of Peptide Synthesis, Vol. I, pages 76-128). Thismethod of production is however inferior to that of the presentinvention.

On attempting to obtain some of the penicillins according to theinvention via the acid chlorides, prepared in the usual manner from theacids (formula (55)) and thionyl chloride, and 6-aminopenicillanic acid,we obtained a mixture of several penicillins amongst which the desiredpenicillin, [identified by a preparation via a different, unambiguousroute] from ampicillin and the corresponding acid chloride A--CO--Cl;compare formula (55) was either not present at all or only present invery small amounts. This was deduced from a comparison of the "in vitro"bacterial spectra and of the thin layer chromatogram. In an experimentto obtain the penicillins according to the invention via the mixedanhydrides, prepared in the usual manner from the acids by means ofchloroformic acid ethyl ester, and aminopenicillanic acid, it was onlypossible to isolate ethoxycarbonylpenicillin in a yield of 20%.

The penicillins of the present invention can also be produced byreacting a compound of the formula: ##EQU17## wherein B and *C are asabove defined,

or a condensation product of such a compound with a carbonyl compound,preferably acetone [U.S. Pat. No. 3,198,804], the said condensationproduct being of the formula: ##EQU18## wherein B and *C are as abovedefined,

(in the preferred case where the carbonyl is acetone, G is methyl)

or a compound of the formula: ##EQU19## wherein B is as above defined;and

R₄, r₅ and R₆ are alkyl with up to 6 carbon atoms, at a temperature of-20°C to +50°C with a compound of the formula: ##EQU20## wherein X, Y,Z, E and Q are as above defined; and

W is halogen or an azide group;

in a solvent and in the presence of a base when a compound of formula(62) or (63) is used, and in an anhydrous solvent free of hydroxylgroups with or without the presence of a base when a compound of formula(64) or (65) is used.

If a compound of the formulae (62) or (63) is used as the startingmaterial for the synthesis of a penicillin according to the invention,and is reacted with a compound of the formulae (66), (67) or (68), thereactions can for example be carried out in a mixture of water and oneor more organic solvents miscible with water, such as acetone,tetrahydrofurane, dioxane, acetonitrile, dimethylformamide,dimethylsulphoxide or isopropanol. At the same time, the pH of thereaction mixture is for example kept between 6.5 and 8.0 by adding abase or by the use of a buffer solution. The reaction according to theinvention can however also be carried out in a different pH range, forexample between 4.5 and 9.0 or at pH 2.0-3.0. It is furthermore possibleto carry out the reaction in a solvent immiscible with water, forexample chloroform or methylene chloride, with the addition of,preferably, triethylamine, diethylamine or N-ethylpiperidine.Furthermore, the reaction can be carried out in a mixture of water and asolvent which is immiscible with water such as, for example, ether,chloroform, methylene chloride, carbon disulphide, isobutyl methylketone, acetic acid ethyl ester or benzene, in which case it isdesirable to stir the mixture vigorously and to maintain the pH valuebetween 4.5 and 9.0 or, for example, 2.0 and 3.0, by adding bases or bythe use of a buffer solution.

If a compound of the formula (64) or (65) is used as the startingmaterial for the synthesis, and this substance is reacted with acompound of the formula (66), (67) or (68), the process must be carriedout in a solvent which is anhydrous and free of hydroxyl groups. Suchsolvents are for example methylene chloride, chloroform, benzene,tetrahydrofurane, acetone and dimethylformamide. In this case, theaddition of a base is not necessary, but in individual cases the yieldand purity of the products can be improved thereby. Admittedly, theconverse effect is also possible. The base which is optionally addedmust either be a tertiary amine, such as pyridine or triethylamine, or asecondary amine which is difficult to acylate as a result of sterichindrance, such as dicyclohexylamine. The number of usable bases ishence almost unlimited.

As in most chemical reactions, higher or lower temperatures than thoseindicated in the Examples can be used. If, however, the values given inthe Examples are significantly exceeded, side-reactions, which reducethe yield or unfavourably influence the purity of the products, willincreasingly occur. On the other hand, excessively lowered reactiontemperatures so greatly reduce the reaction speed that reductions inyield can occur. Reaction temperatures in the range of -20°C to +50°Care therefore preferred, and a temperature of about 0°C to +20°C isparticularly preferred.

The reactants can be reacted with one another in equimolar amounts. Itcan however be desirable to use one of the two reactants in excess, inorder to facilitate the purifications, or preparation in a pure form, ofthe desired penicillin, and to increase the yield. For example, thecompounds of the formulae (62) or (63) can be employed in an excess of0.1 to 0.3 mol equivalents, and less decomposition of the reactants ofthe formulae(66), (67) or (68) in the aqueous solvent mixture canthereby be achieved. The excess of the reactants of the formulae (62) or(63) can be easily removed when working up the reaction mixture, becauseof their good solubility in aqueous mineral acid. On the other hand,however, the reactants of the formulae (66), (67) and (68) can alsoadvantageously be employed in an excess of, for example, 0.1 to 1.0 molequivalents. As a result of this, the reactants, for example of theformulae (62) or (63), are better utilized, and the decomposition of thereactants of the formulae (66), (67) or (68) which takes place as aside-reaction in aqueous solvents, is compensated. Since the compoundsof the formulae (66), (67) or (68) which are added in excess rapidlychange, in water, into neutral amides, ureas or thioureas which caneasily be removed, the purity of the penicillins is thereby hardlyimpaired.

The amount of the base added is determined inter alia by the desiredmaintenance of a particular pH. Where a pH measurement and adjustment isnot carried out, or is impossible or pointless because of the absence ofsufficient amounts of water in the diluent, 2 mol equivalents of baseare preferably added in the case where a compound of the formulae (62)or (63) is used, and either no base at all or, preferably 1 molequivalent of base is added in the case where a compound of the formulae(64) or (65) is used.

The working up of the reaction batches for the manufacture of thepenicillins according to the invention, and of their salts, can bethroughout carried out in the manner generally known for penicillins.

The compounds of the formula (62) used as the starting material in thepresent invention can, as regards the configuration at the asymmetricalcenter in the side chain (: *C), be in the D(-)- = R-form or L(+)- =S-form. They are described in German Pat. Specification No. 1,156,078,in U.S. Pat. Nos. 3,342,677, 3,157,640, 2,985,648 and 3,140,282, inSouth African Pat. No. 68/0290 and (an anhydrous form) in U.S. Pat. No.3,144,445. All crystal forms and configurations of the compounds of theformula (62) are suitable for use as the starting material for thereaction according to the invention. The compounds of the formulae (63),(64) or (65) used as the starting material in the present invention,can, as regards the configuration at the asymmetrical center in the sidechain (: *C), also occur in the D(-)- = R-form or L(+)- = S-form. Theconfiguration of the asymmetrical centers of the 6-aminopenicillanicacid nucleus in the compounds of the formulae (62), (63), (64) and (65)should be identical with the corresponding asymmetrical centers of the6-aminopenicillanic acid, which has, for example, been obtained frompenicillin-G by fermentative processes.

The production of the compounds of the formulae (64) and (65), used asthe starting material, is described in Netherlands Pat. No. 68/18057.

The compounds of the formulae (66) and (67) used as starting materialsin the above process can be produced if W is halogen, according toprocesses which are described in German Offenlegungsschrift No. 1 793287, in German Pat. No. 1,259,871, in U.S. Pat. Nos. 3,275,618 and3,337,621, and in Japanese Pat. No. 434 247.

Furthermore compounds of the formulae (66) and (67) have been prepared,if W is halogen, from the corresponding amides after metallization withmethyl-lithium and subsequent reaction with phosgene. Such preparationsare described in more detail in the examples.

The production of the compounds of the formula (68), to be used as thestarting material, - where W is halogen - is illustrated in Examples No.144B and 147 B/C. It can also be carried out in the same manner asdescribed in the examples.

The sales of the penicillines of the present invention can be obtainedin a manner per se known, for example by reacting the free acid with asuitable base.

The chemotherapeutic activity of the new penicillins was tested in vivoand in vitro. The in vitro inhibition values (MIC = minimum inhibitionconcentration (see Tables 1 and 2) were determined in a liquid medium inthe test tube series dilution test, with readings being taken after 24hours' incubation at 37°C. The MIC is indicated by the non-turbid testtube in the dilution series. A complete medium of the followingcomposition was used as the nutrient medium:

    Lab Lemco (OXOID)    10       g                                               Peptone (DIFCO)      10       g                                               NaCl                 3        g                                               D-(+)-Dextrose (MERCK)                                                                             10       g                                               Buffer pH 7.4        1000     ml.                                         

The spectrum of action encompasses both Gram-negative and Gram-positivebacteria. The particular advantage of the penicillins according to theinvention is that they are effective both in vitro (see Tables 1 and 2)and in animal experiments against ampicillin-resistant andcarbenicillin-resistant Klebsiella bacteria and againstampicillin-resistant Proteus bacteria. Furthermore, ampicillin-resistantvarieties of pseudomonas are attacked in vitro and in vivo. Theconcentrations required for destruction of the bacteria are reached inthe serum after parenteral administration.

The effect, which is generally excellent, is achieved both on a singleadministration and on repeated administration. The penicillins accordingto the invention are stable to acid. Some of the new penicillins arevery well tolerated, which is made particularly clear through theextremely high dose which in these cases is tolerated, withoutcomplication, on intravenous administration into the vein of the tail.

                                      Table 1                                     __________________________________________________________________________    (MIC in units/ml) Bacterial Strains                                           __________________________________________________________________________                                                              Strep-                 E. Coli          Proteus vulg.                                                                           Klebsiella                                                                              Psdm. aerug.                                                                            Staph.                                                                                toc.us              Peni-                                                     faec.               cillin                                                    ATCC                No.*                                                                             14  A 261                                                                             C 165                                                                              183/58                                                                            1017 3400 K 10 63   Bonn Walter                                                                             1777 E                                                                            133 9790                __________________________________________________________________________    1  25  >400                                                                              100  100 400  200   50  50   400  200      1.6 200                 2  3.1 400 12.5 12.5                                                                              100  25    50  50   100  100      ˜0.8                                                                        200                 4  0.8-4                                                                             100-                                                                              4-20 4-20                                                                              4-20 4-20  20-100                                                                            20-100                                                                             20-100                                                                             20-100   <0.8                                                                              100-500                    500                                                                    5      100-                                                                              4-20          20-100    20-100    20-100   <0.8                                                                              100-500                    500                                                                    7  100-500                                                                           >500                                                                              100-500                                                                            100-                                                                              ˜500                                                                         100- 500                                                                            >500                                                                              >500 100-500                                                                            >500 100-                                                                              0.8-4                                                                             100-500                500          500                               500                         8  >500                                                                              >500                                                                              >500 >500                                                                              >500 >500  >500                                                                              >500 >500 >500 100-                                                                              4-20                                                                              >500                9  20-100                                                                            >500                                                                              100-500                                                                            100-                                                                              >500 >500  >500                                                                              >500 >500 >500     0.8-4                                                                             ˜500                          500                                                           10 B                                                                             12.5                                                                              >400                                                                              50   50  200  200   50  50   200  200  400 1.6 100                 11 C                                                                             6.3 >400                                                                              50   12.5                                                                              100  100   50  100  400  200  400 1.6 200                 12 6.3 >400                                                                              50   12.5                                                                              100  100   50  100  400  200  400 1.6 200                 14 4-20                                                                              >500                                                                              20-100                                                                             20-100                                                                            100-500                                                                            ˜100                                                                          20-100                                                                            20-100                                                                             100-500                                                                            100-500  0.8-4                                                                             100-500             15 20-100                                                                            >500                                                                              100-500                                                                            100-                                                                              >500 >500  >500                                                                              >500 >500 >500     0.8-4                                                                             >500                                500                                                           17 4-20                                                                              >500                                                                              20-100                                                                             20-100                                                                            >500 100- 500                                                                            20-100                                                                            20-100                                                                             100-500                                                                            100-500  <0.8                                                                              20-100              18 4-20                                                                              >500                                                                              20-100                                                                             20-100                                                                            100-500                                                                            100-500                                                                             20-100                                                                            20-100                                                                             100-500                                                                            100-500  0.8-4                                                                             ˜100          20     >500                                                                              20-100        100-500   20-100    100-500  <0.8                                                                              20-100              21     >500                                                                              20-100        20-100    20-100    100-500  <0.8                                                                              100-500             22     >500                                                                              4-20          4-20      20-100    20-100   <0.8                                                                              ˜20           23     >500                                                                              100-500       >500      >500      >500     0.8-4                                                                             100-500             24 6.3 >400                                                                              25   25  100  50    50  100  100  100      ˜1.6                                                                        200                 27 100 >400                                                                              200  200 >400 >400  >400                                                                              >400 >400 >400 >400                                                                              6.3 >400                28 100 >400                                                                              200  400 >400 >400  >400                                                                              >400 >400 >400 >400                                                                              12.5                                                                              >400                29 3.1 >400                                                                              6.3  3.1 12.5 12.5  200 100  25   50   200 <                                                                                 100                 30 4-20                                                                              >500                                                                              20-100                                                                             20-100                                                                            100- 100-500                                                                             100-500                                                                           100-500                                                                            100-500                                                                            100-500  0.8-4                                                                             20-100                                  500                 approx.                               31 20-100                                                                            >500                                                                              100-500                                                                            20-100                                                                            100- 100-500                                                                             100-500                                                                           100-500                                                                            500  100-500  0.8-4                                                                             >500                                    500                                                          approx.          approx.                                                   32 20  >500                                                                              20-100                                                                             20-100                                                                            100  100-500                                                                             100-500                                                                           approx. 100                                                                        100-500                                                                            100-500  approx.                                                                           100-500                                                                   0.3                     33     100-                                                                              4-20     4-20           4-20      4-20     <0.8                                                                              20-100                 approx.                                                                           500                                   approx.                          35 4   100-                                                                              20-100                                                                             4-20                                                                              20-100                                                                             20-100                                                                              20-100                                                                            20-100                                                                             4-20 20       <0.8                                                                              20-100                     500                                                                    36     >500                                                                              100-500  >500           >500      >500     4-20                                                                              100-500             37 <0.8                                                                              >500                                                                              0.8-4                                                                              0.8-4                                                                             4-20 4-20  20-100                                                                            4-20 4-20 4-20     <0.8                                                                              20-100              38 0.8-4                                                                             >500                                                                              4-20 4-20                                                                              20-100                                                                             20-100                                                                              20-100                                                                            20-100                                                                             20-100                                                                             20-100   <0.8                                                                              100-500             44 6.25                                                                              400 25   25  50   25    50  50   50   50       1.6 100                 45 6.25                                                                              >400                                                                              25   6.25                                                                              100  100   100 100  25   12.5 400 <0.78                                                                             50                  46 6.25                                                                              >400                                                                              50   12.5                                                                              25   50    100 50   25   25   200 1.56                                                                              50                  47 3.12                                                                              >400                                                                              25   6.25                                                                              50   100   100 50   12.5 12.5 200 <0.78                                                                             50                  48 A                                                                             3.12                                                                              >400                                                                              12.5 6.25                                                                              25   50    100 50   25   12.5 200 <0.78                                                                             25                  51 3.12                                                                              400 12.5 12.5                                                                              25   25    100 50   12.5 12.5 400 <0.78                                                                             25                  52 3.12                                                                              >400                                                                              12.5 6.25                                                                              --   --    100 --   12.5 12.5 200 <0.78                                                                             --                  53 3.12                                                                              400 6.25 12.5                                                                              6.25 12.5  50  25   6.25 12.5 200 <0.78                                                                             12.5                54 6.25                                                                              >400                                                                              25   6.25                                                                              200  100   100 100  12.5 25   200 <0.78                                                                             50                  55 6.25                                                                              >400                                                                              25   12.5                                                                              100  100   100 100  12.5 25   200 <0.78                                                                             50                  __________________________________________________________________________     *The numbers in this column are the numbers of the Examples in which the      penicillin and its production are described.                             

                                      Table 2                                     __________________________________________________________________________    MIC in units/ml                                                               __________________________________________________________________________    Bacterial Strains                                                             __________________________________________________________________________    Peni-                                   Pseudomonas                                                                            Staph.   Strep.              cillin                                                                            E. coli         Prot. vulg.                                                                             Klebsiella                                                                              aerug.   aureus   faec.               No. 14  A 261                                                                             C 165                                                                             183/58                                                                            1017 3400 K 10 63   Bonn                                                                              Walter                                                                             1777E                                                                              133 ATCC                                                                          9790                __________________________________________________________________________    Ampi-                                                                             ˜0.8                                                                        >400                                                                              6.25                                                                              200 400  >400 100-200                                                                            100-200                                                                            200 200  200  <1.0                                                                              12.5                cillin                                                                        59  1.56                                                                              >400                                                                              6.25                                                                              3.12                                                                              6.25 12.5 25   50   12.5                                                                              25   100  <0.78                                                                             100                 60  6.25                                                                              >400                                                                              25  12.5                                                                              25   50   100  50   25  50   50   <0.78                                                                             100                 61  3.12                                                                              >400                                                                              6.25                                                                              6.25                                                                              25   25   100  50   12.5                                                                              25   200  <0.78                                                                             50                  62  1.56                                                                              400 6.25                                                                              3.12                                                                              6.25 6.25 100  100  12.5                                                                              25   400  <0.78                                                                             100                 63  <0.78                                                                             400 1.56                                                                              <0.78                                                                             1.56 3.12 50   50   6.25                                                                              12.5 200  <                                                                                 5078                64  3.12                                                                              >400                                                                              25  25  25   100  100  100  25  50   50    1.56                                                                             100                 65  <0.78                                                                             400 3.12                                                                              1.56                                                                              3.12 6.25 12.5 12.5 12.5                                                                              12.5 50   <0.78                                                                             50                  66  3.12                                                                              >400                                                                              12.5                                                                              50  50   100  50   50   6.25                                                                              12.5 50   <0.78                                                                             25                  67  1.56                                                                              400 6.25                                                                              1.56                                                                              6.25 6.25 100  100  25  50   400  <0.78                                                                             100                 68  3.12                                                                              >400                                                                              12.5                                                                              6.25                                                                              12.5 25   50   25   12.5                                                                              12.5 50   <0.78                                                                             50                  69  1.56                                                                              400 6.25                                                                              3.12                                                                              12.5 25   50   25   12.5                                                                              100       <0.78                                                                             100                 70  3.12                                                                              200 6.25                                                                              3.12                                                                              12.5 12.5 25   12.5 12.5                                                                              100       <0.78                                                                             100                 71  >400                                                                              >400                                                                              >400                                                                              >400                                                                              >400 >400 >400 >400 >400                                                                              400       200 >400                72  6.25                                                                              400 25  12.5                                                                              50   200  100  50   50  400       <0.78                                                                             100                 73  3.12                                                                              200-                                                                              6.25                                                                              1.56                                                                              6.25 12.5 25-50                                                                              12.5-25                                                                            12.5                                                                              ˜50 0.78                                                                              50-100                      400                                                                   74  100 >400                                                                              >400                                                                              >400                                                                              >400 >400 >400 >400 >400                                                                              >400      25  >400                75  <0.8                                                                              100<                                                                              0.8<4                                                                             0.8<4                                                                             4<20 0.8<4                                                                              20<100                                                                             4<20 4<20                                                                              4<20      0.8 20<100                      500                                                                   76  0.8<4                                                                             100<                                                                              4<20                                                                              ˜4                                                                          4<20 20<100                                                                             20<100                                                                             20<100                                                                             4<20                                                                              20<100    <0.8                                                                              20<100                      500                                                                   83  3.12                                                                              400 6.25                                                                              6.25                                                                              25   6.25 25   50   50  100       <0.78                                                                             100                 86  12.5                                                                              >400                                                                              25  50  50   50   100  50   25  50        <0.78                                                                             100                 87  4<20                                                                              100<                                                                              20< 20< 20<100                                                                             20<100                                                                             20<100                                                                             20<100                                                                             4<20                                                                              20<100    <0.8                                                                              20<100                      500 100 100                                                           88  1.56                                                                              400 6.25                                                                              3.12                                                                              12.5 6.25 50   25   25  50        <0.78                                                                             50                  89  1.56                                                                              400 6.25                                                                              1.56                                                                              3.12 12.5 25   12.5 25  50        <0.78                                                                             100                 90  6.25                                                                              400 12.5                                                                              12.5                                                                              12.5 25   50   25   25  50   50       100                 91      100<                                                                              0.8<4   0.8<4          4<20     4<20      <0.8                                                                              20<100                      500                                                                   92 B    >500                                                                              4<20    20<100         20<100   20<100    <0.8                                                                              20<100              93 B    >500                                                                              4<20    20<100         20<100   20<100    <0.8                                                                              20<100              94  12.5                                                                              >400                                                                              50  100 100  50   200  200  100 100       3.12                                                                              200                 96  6.25                                                                              >400                                                                              12.5                                                                              25  50   50   200  200  25  25   400  1.56                                                                              25                  97  6.25                                                                              >400                                                                              25  6.25                                                                              25   25   400  50   25  50                                98  3.12                                                                              >400                                                                              6.25                                                                              6.25                                                                              12.5 25   400  400  12.5                                                                              25   200  <0.78                                                                             100                 99 B    >500                                                                              20-100  approx.        <500     100-500   <0.8                                                                              100-                                    500                                   500                 101 B   >500                                                                              20-100  100-500        100-500  100-500   <0.8                                                                              approx.                                                                       20                  102     >500                                                                              4<20    4<20           20<100   4<20      <0.8                                                                              4<20                103     >500                                                                              4-20    100-500   100-      100-          <0.8                                                                              20-100                                            500       500                                   105 B   >500                                                                              4-20    <500           100-500  >500      <0.8                                                                              20-100              107 <0.8                                                                              20< <0.8                                                                              <0.8                                                                              0.8-4                                                                              0.8-4                                                                              ˜4                                                                           4-20 0.8-4                                                                             0.8-4                                                                              20-100                                                                             <0.8                                                                              4-20                        100                                                                   108     >500                                                                              4-20    20-100         100-500                                                                            0.8-4                                                                             20-100    <0.8                                                                              ˜20           109     >500                                                                              4-20    20-100         100-500  50-100    0.8 4-20                110 0.8-4                                                                             100-                                                                              4-20                                                                              4-20                                                                              4-20 4-20 4-20 4-20 20- 20-100                                                                             20-100                                                                             0.8 4-20                        500                             100                                   111 <0.8                                                                              20-100                                                                            0.8-4                                                                             <0.8                                                                              0.8-4                                                                              0.8-4                                                                              4-20 4-20 4-20                                                                              4-20 4-20 0.8 4-20                112 <0.8                                                                              20-100                                                                            0.8-4                                                                             <0.8                                                                              0.8-4                                                                              0.8-4                                                                              4-20 4-20 4-20                                                                              4-20 20-100                                                                             0.8 4-20                113         0.8-4   4-20           100- 500 4-20 100-500                                                                            0.8                     114         4-20    20-100         100-500  4-20 100-500                                                                            0.8                     115         20-100  20-100         100-500  20-100                                                                             100-500                                                                            0.8                     116         4-20    4-20           20-100   approx.                                                                            100-500                                                                            0.8                                                                 20                                117 <0.78                                                                             50  1.56                                                                              1.56                                                                              3.12 3.12 6.25 12.5 12.5                                                                              12.5 12.5 0.8 50                  118 12.5                                                                              >400                                                                              50  200 100  200  100  200  200 200  100  1.6 50                  119 25  >400                                                                              200 400 >400 >400 400  >400 >400                                                                              >400 200  1.6 100                 121 6   >400                                                                              50  100 100  200  25   100  100 100  100  <0.8                                                                              100                 122 12.5                                                                              >400                                                                              50  200 100  400  50   100  200 400  400  1.6 100                 123 3.12                                                                              >400                                                                              25  12.5                                                                              50   100  50   100  50  100  25   <0.8                                                                              200                 124 3.12                                                                              >400                                                                              12.5                                                                              25  50   50   50   50   50  100  25   <0.78                                                                             200                 125 3.12                                                                              >400                                                                              25  50  50   100  200  100  50  100  50   3.12                                                                              200                 126 12.5                                                                              >400                                                                              50  50  100  100  100  200  100 200  100  1.66                                                                              200                 127 0.78                                                                              50  3.12                                                                              1.56                                                                              3.12 6.25 12.5 12.5 12.5                                                                              25   12.5 <0.78                                                                             25                  128 0.78                                                                              50  1.56                                                                              <0.78                                                                             1.56 6.25 6.25 6.25 6.25                                                                              12.5 12.5 <0.78                                                                             50                  129 0.78                                                                              50  1.56                                                                              1.56                                                                              3.12 6.25 6.25 6.25 6.25                                                                              12.5 6.25 <0.78                                                                             50                  130 12.5                                                                              >400                                                                              100 100 200  400  25   50   200 200       <0.8                                                                              50                  131 0.8 20-100                                                                            <0.8                                                                              <0.8                                                                              0.8-4                                                                              0.8-4                                                                              0.8-4                                                                              4-20 0.8-4                                                                             0.8-4                                                                              20-100                                                                             <0.8                                                                              4-20                132 0.8 >400                                                                              0.8-4                                                                             <0.8                                                                              4-20 0.8-4                                                                              4-20 20-100                                                                             4-20                                                                              4-20 20-100                                                                             <0.8                                                                              4-20                134 3.1 >400                                                                              25  25  12.5 50   50   200  100 50   200  3.1 100                 135 12.5                                                                              400 50  25  25   100  100  400  400 100  100  <0.8                                                                              200                 138 6.25                                                                              200 25  12.5                                                                              25   100  50   50   25  100  12.5 <0.8                                                                              50                  140 0.8 50  3.1 1.6 3.1  6.25 12.5 25   12.5                                                                              12.5      <0.8                                                                              12.5                141 0.8 50  3.1 1.6 3.1  3.1  6.25 12.5 12.5                                                                              6.25                              142 0.8 50  3.1 1.6 3.1  12.5 12.5 25   25  12.5      <0.8                                                                              25                  143 12.5                                                                              >400                                                                              50  50  200  400  50   100  200 200       <0.8                                                                              100                 144 1.56                                                                              400 6.25                                                                              50  12   25   50   50   6.25                                                                              12.5 200  <0.8                                                                              25                  147A                                                                              12.5                                                                              >400                                                                              50  100 50   200  200  100  25  200  100  <0.8                                                                              50                  __________________________________________________________________________

The activity spectrum includes both Gram-negative and Gram-positivebacteria. The paticular advantage of the penicillins according to theinvention is that they are effective both in vitro (Tables 1 and 2) andin animal experiments (Table 3) against ampicillin-resistant andcarbenicillin-resistant Klebsiella bacteria and againstampicillin-resistant Proteus bacteria. Furthermore, they act onampicillin-resistant Pseudomonas varieties in vitro and in vivo. Theconcentrations required for destroying the bacteria are reached in theserum after parenteral administration (Table 4). Table 5 shows thedecrease in the number of ampicillin-resistant Proteus bacteria presentin the blood after intraperitoneal infection and subcutaneousadministration of 50,000 units/kg of penicillin. The excellent effect ofsome of the new penicillins against Gram-positive bacteria is shown inTable 3. The excellent effect is achieved both on a singleadministration and also on multiple administration. The resorption ofthe new penicillins often takes place very rapidly after subcutaneousadministration (Table 4), and the peak values are often reached within10 minutes. Elimination is equally rapid in both these cases. Thesubstances according to the invention are stable to acid; as examples,penicillins No. 59, No. 66 and No. 83 may be quoted, which remainmicrobiologically active at pH 1 for over one hour. Table 6 shows thatthe new penicillins are excellently tolerated, which is shownparticularly clearly by the extremely high dose which is toleratedwithout complications on intravenous administration into the vein of thetail. Penicillin No. 66 may here be very particularly quoted as anexample.

The experiments on animals (see Table 3) were carried out with whitemice of the CF1 strain. The infection took place intraperitoneally withthe particular bacterium indicated.

                                      TABLE 3                                     __________________________________________________________________________    Number of surviving mice in % after intraperitoneal infection and             subcutaneous therapy,                                                         30 minutes and 90 minutes after infection                                     Peni-                                                                            Dose:                                                                      cillin                                                                           2 × 3000 units/mouse                                                                2 × 200 units/mouse                                                                 4 × 3000 units/mouse                                                                2 × 3000 units/mouse                                                                2 × 3000                                                                units/mouse                No:-                                                                             E.coli C 165                                                                              Staph. aureus 133                                                                         Psdm. aerug. Walter                                                                       Klebsiella 63                                                                             Proteus vulg. 1017            (Ampicillin-                                                                              (Ampicillin-                                                                              (Ampicillin-                                                                              (Ampicillin- and                                                                          (Ampicillin-                  sensitive)  sensitive)  resistant)  Carbenicillin-                                                                            resistant)                                                        resistant)                             __________________________________________________________________________       1  2  3  5  1  2  3  5  1  2  3  5  1  2  3  5  1  2  3  5                    day                                                                              days                                                                             days                                                                             days                                                                             day                                                                              days                                                                             days                                                                             days                                                                             day                                                                              days                                                                             days                                                                             days                                                                             day                                                                              days                                                                             days                                                                             days                                                                             day                                                                              days   days                                                                   days                    59 70 60 60 60 90 70 70 70             100                                                                              90 30    100                                                                              100    100                                                                    100                     90 100                                                                              90 90 90                         90 70 0     100                                                                              80     80                                                                     80                      62 80 70                               100                                                                              100                                                                              40    70 50     50                                                                     50                      63 80 60 60 60                         100                                                                              100                                                                              30    80 70     70                                                                     70                      65 90 60 60 60 90 80 70 70             100                                                                              100                                                                              10    100                                                                              100    100                                                                    100                     73 70 50 40 40 80 70 50 40 50 30 10    100                                                                              80 0     100                                                                              100    100                                                                    100                     66 100                                                                              60 50 50 100                                                                              90 70 70 30          90 90 0     100                                                                              100    100                                                                    100                     67 80 50 40 40             50          100                                                                              80 10    100                                                                              100    100                                                                    90                      83 90 60 60 60 80 70 70 70 70 20       100                                                                              100                                                                              60    100                                                                              100    100                                                                    100                     94 50 30 30 30                         80 30       100                                                                              100    100                                                                    100                     75 90 80 80 80                         100                                                                              100                                                                              100                                                                              20 60 10                      Ampi-                                                                         cillin                                                                           100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100            0  0  0  0  0  0      0                                                                      0                       Car-                                                                          beni-                                                                         cillin                                 0  0  0  0  100                                                                              100    100                                                                    100                     __________________________________________________________________________

Continuation of Table 3.

Number of surviving mice in % (after intraperitoneal infection andsubcutaneous therapy) after the indicated number of days.

    __________________________________________________________________________    Bacterial Strains                                                                        Penicillin                                                                            Dose*.sup.)                                                                       1st 2nd 3rd 5th day                                    __________________________________________________________________________    E.coli C 165                                                                             No:-144 A   80  80  80  80                                         E. coli C 165                                                                            Carbenicillin                                                                         A   70  50  50  50                                         Prot.vulg. 1017 I                                                                        No:-144 A   70  50  50  50                                                    Carbenicillin                                                                         A   50  50  50  50                                                    Ampicillin                                                                            A   0   0   0   0                                                     No:-147 B   100 100 100 100                                        Klebsiella 63                                                                            No:-144 B   70  30  0                                                         Carbenicillin                                                                         B   0                                                                 Ampicillin                                                                            B   0                                                                 Cephalothin                                                                           B   0                                                                 No:-147 C   100 100 40  10                                         Pseudm.aer.                                                                              No:-144 D   100 20  20  20                                         Walter                                                                                   Carbenicillin                                                                         D   80  20  20  20                                                    Ampicillin                                                                            D   0                                                                 Cephalothin                                                                           D   0                                                      Pseudomon.                                                                    aer. F 41  No:-144 E   100                                                               Carbenicillin                                                                         E   0                                                      Pseudomon.                                                                    aer. F 41  No:-144 F   100                                                               Carbenicillin                                                                         F   20                                                     Pseudomon.                                                                    aer. F 41  No:-144 G   100                                                               Carbenicillin                                                                         G   70                                                     Pseudomon.                                                                    aer. F 41  No:-144 H   100                                                               Carbenicillin                                                                         H   70                                                     Klebsiella 63                                                                            No:-144 A   30                                                                Carbenicillin                                                                         A   0                                                      Klebsiella 63                                                                            No:-144 B   100                                                               Carbenicillin                                                                         B   0                                                      Klebsiella 63                                                                            No:-144 C   100                                                               Carbenicillin                                                                         C   0                                                      __________________________________________________________________________    *.sup.) Dose A = 37,500 units/kg,                                                              30 and 90 minutes after infection                            Dose B = 75,000 units/kg,                                                                      30 and 90 minutes after infection                            Dose C = 150,000 units/kg,                                                                     30 and 90 minutes after infection                            Dose D = 150,000 units/kg,                                                                     0.5, 2, 4 and 6 hours after                                                   infection                                                    Dose E = 50,000 units/kg,                                                                      30 minutes before and 2, 4 and 6                                              hours after infection                                        Dose F = 75,000 units/kg,                                                                      30 minutes before and 2, 4 and 6                                              hours after infection                                        Dose G = 150,000 units/kg,                                                                     30 minutes before and 2, 4 and 6                                              hours after infection                                        Dose H = 200,000 units/kg,                                                                     30 minutes before and 2, 4 and 6                                              hours after infection.                                   

Table 4

Serum lever after subcutaneous ("s.c.") administration to white mice, inunits/ml of serum, measured from the microbiological activity againstProteus vulgaris 1017 (ampicillin-resistant).

    __________________________________________________________________________    Peni-                                                                             Dose  Concentration in the serum; number of minutes                       cillin                                                                            (s.c.)                                                                              after administration of the dose                                    No:-      10 mins.                                                                            15 mins.                                                                            20 mins.                                                                            30 mins.                                                                            60 mins.                                    __________________________________________________________________________    59  150.000     25 units    20 units                                                                            <2 units                                        units                                                                     64  50.000                                                                              50 units    10 units                                                    units                                                                     64  150.000     42 units    26 units                                                                            <10 units                                       units                                                                     __________________________________________________________________________

TABLE 5

Reduction in number of bacteria/ml of blood after subcutaneousadministration of Penicillin No. 83. Infection took placeintraperitoneally with Proteus vulgaris 1017, 8 × 10⁵ /mouse;ampicillin-resistant.

                                      Table 5                                     __________________________________________________________________________    Reduction in number of bacteria/ml of blood after subcutaneous                administration of Penicillin No. 83.                                          Infection took place intraperitoneally with Proteus vulgaris 1017, 8          × 10.sup.5 /mouse; ampicillin-resistant.                                             Number of bacteria after infection, measured after                            infection:                                                                    30 mins.                                                                             60 mins.                                                                             90 mins.                                                                             120 mins.                                                                            150 mins.                                                                            180 mins.                     __________________________________________________________________________    Control      3 × 10.sup.4                                                                   2 × 10.sup.4                                                                   2 × 10.sup.4                                                                   --     7 × 10.sup.4                                                                   5 × 10.sup.4            Administration of:                                                            1 × 50,000 units/kg                                                     subcutaneously,                                                                            9 × 10.sup.3                                                                   7 × 10.sup.3                                                                   2 × 10.sup.3                                                                   1 × 10.sup.3                                                                   3 × 10.sup.3                                                                   8 × 10.sup.3            30 minutes after                                                              infection                                                                     Administration of:                                                            1 × 50,000 units/kg                                                     subcutaneously, after      approx.                                            30 minutes, and a                                                                          2 × 10.sup.4                                                                   8 × 10.sup.3                                                                   5 × 10.sup.3                                                                   2 × 10.sup.2                                                                   <10.sup.1                                                                            <10.sup.1                     further 50,000 units/                                                         kg after 90 minutes.                                                          __________________________________________________________________________

The Table shows that a dose of 50,000 units/kg, administeredsubcutaneously, already drastically reduces the number of bacteria inthe blood; additionally, it shows that the double subcutaneousadministration of 50,000 units/kg causes elimination of the bacteria.

                  Table 6                                                         ______________________________________                                                 Acute toxicity (LD.sub.50) in white mice                                      after intravenous injection into the vein                                     of the tail, in mg/kg                                                ______________________________________                                        Penicillin                                                                    No.                                                                           66         >4000                                                              60         1500                                                               86         >3000                                                              83         >1200                                                              94         4000                                                               75         1500                                                               Carbenicillin                                                                            2700                                                               Dicycloxacillin                                                                          900                                                                ______________________________________                                    

The comparison shows that the new penicillins are clearly superior tothe commercially available products dicycloxacillin and carbenicillin onintravenous injection of a single dose.

The invention further relates to the pharmaceutical use of the newpenicillins and their pharmaceutically acceptable salts.

Accordingly, the present invention provides an antibiotic pharmaceuticalcomposition containing as an active ingredient at least one of thepenicillins of the formula (1), or a pharmaceutically acceptablenon-toxic salt thereof in combination with a pharmaceutically acceptablesolid or liquid diluent or carrier as hereinafter defined.

In the present specification the expression "pharmaceutically acceptablediluent or carrier" means a non-toxic substance that when mixed with theactive ingredient or ingredients renders it suitable for administration.The expression preferably excludes water and low-molecular weightorganic solvents commonly used in chemical synthesis, except in thepresence of other pharmaceutically necessary ingredients such as saltsin correct quantities to render the composition isotonic, buffers,surfactants, coloring and flavoring agents, and preservatives. Examplesof suitable liquid diluents and carriers are vegetable oils, polyols,buffered aqueous solutions, isotonic saline aqueous solutions, syrupsand lotion bases. Examples of suitable solid diluents and carriers arestarches, cellulose and its derivatives, sugars, stearates and stearicacid, talc, certain types of alumina, and ointment bases. Examples ofpharmaceutical compositions according to the invention are ointments,pastes, creams, sprays, lotions, aqueous suspensions, elixirs, syrups,drops, granules and powders, either free-flowing or compressed intotablets.

The penicillins and pharmaceutically acceptable salts of the presentinvention may be administered perorally.

One group of preferred pharmaceutical compositions of the invention aretherefore those adapted for oral administration. The diluents andcarriers used are preferably therefore those that adapt the activeingredient or ingredients for oral administration. Examples of suchdiluents and carriers are solid vehicles, excipients and lubricants suchas glucose, lactose and sucrose, corn and potato starch, sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate, powderedgum tragacanth, gelatin, alginic acid, agar, stearic acid, sodiumcalcium and magnesium stearates, sodium lauryl sulphate,polyvinylpyrollidone, sodium citrate, calcium carbonate, dicalciumphosphate, and certain types of alumina.

The pharmaceutical compositions of the invention may also contain othernon-toxic adjuvants and modifiers such as dyes, surfactants, perfumes,flavouring agents, preservatives and biocides.

The compounds of the present invention may also be administeredparenterally for example by intramuscular, subcutaneous or intravenousinjection, or, if necessary, as a continuous drip infusion. A group ofpreferred pharmaceutical compositions of the invention are thereforethose adapted for parenteral injection. The diluents and carriers usedare therefore preferably those that adapt the active ingredient forparenteral administration. Examples of such diluents and carriers aresolvents and suspending diluents such as water and water-miscibleorganic solvents, in particular sesame oil, groundnut oil, aqueouspropylene glycol, and N,N'-dimethyl formamide. A preferred example of apharmaceutical composition of the invention adapted for parenteraladministration is a sterile isotonic saline aqueous solution of theactive ingredient, which may be buffered with a pharmaceuticallyacceptable buffer. The solution may be rendered isotonic in any knownmanner, for example by the incorporation of sodium chloride and/orglucose. Such solutions can be administered as a single dose or as acontinuous drip infusion, or divided into a series of doses.

In oral and parenteral administration a dose of 25,000 to 1,000,000units per kg. body weight is appropriate.

The present invention also provides antibiotic medicaments in dosageunit form as hereinafter defined comprising as an active ingredient atleast one penicillin of formula (1), or a pharmaceutically acceptablenon-toxic salt thereof, either alone or in combination with apharmaceutically acceptable solid or liquid diluent or carrier. In thiscase the diluent or carrier is preferably as defined above but can alsobe water or another common solvent.

The expression "medicament in dosage unit form" as used in the presentspecification means a medicament in the form of discrete portions eachcontaining a unit dose or a multiple or sub-multiple of a unit dose ofthe active ingredient(s); for example, one, two, three or four unitdoses or a half, a third or a quarter of a unit dose. A "unit dose" isthe amount of the active ingredient(s) to be administered on oneoccasion and will usually be a daily dose, or for example a half, athird, or a quarter of a daily dose depending on whether the medicamentis to be administered once or, for example, twice, three times, or fourtimes a day.

The discrete portions constituting the medicament in dosage unit formcan include a protective envelope. The active ingredient can beundiluted and contained in such an envelope, or can be mixed with apharmaceutically acceptable solid or liquid diluent or carrier asdefined above. Such portions can for example be in monolithic coherentform, such as tablets, lozenges, pills, suppositories, or dragees; inwrapped or concealed form, the active ingredients being within aprotective envelope, such as wrapped powders, cachets, sachets,capsules, or ampoules; or in the form of a sterile solution suitable forparenteral injection, such as ampoules of buffered, isotonic, sterile,pyrogen-free aqueous solution; or in any other form known in the art.

As stated above, oral administration is one preferred form ofadministration for the penicillins of formula (1) and theirpharmaceutically acceptable non-toxic salts. Preferred medicaments indosage unit form according to the invention are therefore those adaptedfor oral administration, such as tablets, pills, dragees, capsules, andcachets, as well as wrapped powders containing the active ingredient inpowdered form with a powdered diluent or carrier for suspension in waterbefore being taken.

As stated above, another preferred mode of administration for thepenicillins and their pharmaceutically acceptable non-toxic salts isparenteral administration. Preferred medicaments in dosage unit formaccording to the invention are therefore those adapted for parenteralinjection, such as ampoules containing a measured quantity of a sterileisotonic saline injectable aqueous solution of the new activeingredient, which may be buffered with a pharmaceutically acceptablebuffer. A particularly preferred medicament in dosage unit formaccording to the invention is dry ampoules each containing a unit doseor a multiple or sub-multiple of a unit dose of one of the newpenicillins and pharmaceutically acceptable salts according to theinvention. Such ampoules may be used at the place and time ofadministration for making up parenterally injectable solutions.

The preferred unit dose for parenteral and peroral administration of themedicaments of the invention is 1,250,000 - 90,000,000 units per personof active ingredient.

The following non-limitative examples more particularly illustrate thepresent invention.

The α-aminobenzylpenicillin (ampicillin) used in the examples containedabout 14% of water, but anhydrous α-aminobenzylpenicillin [compare U.S.Pat. No. 3,144,445] can be used equally well.

Unless expressly stated otherwise, "ampicillin" denotes theα-aminobenzylpenicillin having the D(-)- = R-configuration in the sidechain.

The β-lactam content of the penicillins was determined iodometrically inthe following Examples. All substances described here showed an IRspectrum corresponding to their structure. The NMR spectra of thepenicillins were recorded in CD₃ OD solution; the signals indicated inthe Examples correspond to the τ-scale; they agree with the particularstructure.

The figures quoted in the Examples for the effectiveness against certainbacteria (units/ml) are minimum inhibitory concentrations in the testtube series dilution test after 24 hours' incubation.

In the case of the data: "Effectiveness in Animal Experiments," "A"denotes that the particular penicillin is more effective than ampicillinwhen used subcutaneously in mice against Proteus Vulgaris 1017, and "B"denotes that it is more effective than ampicillin and carbenicillinagainst Klebsiella aerobacter 63.

EXAMPLE 1 Sodium D(-)-α-(3-acetyl-3-allyl ureido)-benzylpenicillin:

5.5 parts by weight of D(-)-α-(3-acetyl-3-allyl-ureido)-α-phenylaceticacid were dissolved in 50 parts by volume of dichloromethane, withexclusion of moisture, and 2.0 parts by weight of triethylamine wereadded while cooling. The mixture was now cooled to between -5° and-10°C, and 3.6 parts by weight of tetramethylchloroformamidiniumchloride were added as several portions over the course of a fewminutes. Thereafter, the mixture was stirred for 30 minutes at thistemperature and any insoluble matter was filtered off without thesolution rising to above 0°C. The filtrate was cooled to -10°C and addedall at once to a solution of 4.1 parts by weight of 6-aminopenicillanicacid and 3.4 parts by weight of triethylamine in 50 parts by volume ofdichloromethane, cooled to -10°C. [The aminopenicillanic acid wasstirred for 1.5 hours at room temperature with the triethylamine and2parts by weight of a molecular sieve (Zeolite VS 10-2) which had beenground in a mortar; thereafter, the mixture was filtered while excludingmoisture, and the filtrate was employed for the reaction]. The combinedsolutions were left to stand for 1 hour at 0°C and subsequently pouredinto 100 parts by volume of water. the pH value was adjusted to 6.5, thedichloromethane phase was separated off, and the aqueous phase wascovered with 200 parts by volume of a 1:1 mixture of ethyl acetate andether. Sufficient 2 N hydrochloric acid was added, while stirringvigorously and cooling with ice, to obtain a pH value of 2.0 in theaqueous layer. The organic phase was separated off, washed with 2 × 40parts by volume of water and dried for two hours over MgSO₄ in arefrigerator. 20 parts by volume of a 1 M solution of sodium2-ethylhexanoate in ether containing methanol were now added, themixture was largely concentrated in vacuo at 0°C, the residue was takenup in just sufficient methanol, and the sodium salt of the penicillinwas precipitated by adding excess ether whilst shaking vigorously.

Yield: 67%. β-Lactam content: 81%.

    ______________________________________                                                 C         H         N       S                                        Calculated:                                                                            51.4      5.3       10.9    6.2                                      Found:   51.5      6.0       10.3    5.5                                      ______________________________________                                    

According to the IR spectrum and thin layer chromatogram the product wasidentical with a comparison sample prepared from ampicillin andN-acetyl-N-allylcarbamic acid chloride.

EXAMPLE 2 SodiumD(-)-α-(3-γ-chlorobutyryl-3-methyl-ureido)-benzylpenicillin:

A solution was prepared, as described in Example 1, from 6.25 parts byweight of D(-)-α-(3-γ-chlorobutyryl-3-methyl-ureido)-phenylacetic acidand 3.6 parts by weight of tetramethylchloroformamidinium chloride, andwas kept for 1.5 hours at -5° to -10°C. Thereafter it was combined witha solution of 4.1 parts by weight of 6-aminopenicillanic acid and 3.5parts by weight of triethylamine in dichloromethane, which was storedfor one hour at room temperature. Thereafter the mixture was worked upas described in Example 1.

Yield: 62%. β-Lactam content: 84%.

    ______________________________________                                                 C        H        Cl     N      S                                    Calculated:                                                                            48.0     5.1      6.4    10.2   5.8                                  Found:   48.1     5.2      5.8     9.9   6.4                                  ______________________________________                                    

NMR signals at τ=2.3-2.9 (5 H), 4.45 (1 H), 4.55 (2 H), 5.8 (1 H), 6.4(2 H), 6.75 (3 H), 7.3 (2 H), 7.9 (2 H) and 8.5 ppm (6 H).

EXAMPLE 3

If, in the procedure of Example 2, theD(-)-α-(3-γ-chlorobutyryl-3-methylureido)-phenylacetic acid used thereis replaced by 0.02 mol of:-

D(-)-α-(3-β-chloropropionyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-γ-trifluorobutyryl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-γ-trichlorobutyryl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-γ-trichlorobutyryl-3-γ-chloroethyl-ureido)-phenylacetic acid,

D(-)-α-(3-cinnamoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1,2,5,6,-tetrahydrobenzoyl]-3-methyl-ureido)-phenylaceticacid or

D(-)-α-(3-hexahydrobenzoyl-3-methyl-ureido)-phenylacetic acid,

the following penicillins are obtained in the form of their sodiumsalts:

D(-)-α-(3-β-chloropropionyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-γ-trifluorobutyryl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-γ-trichlorobutyryl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-γ-trichlorobutyryl-3-γ-chloroethyl-ureido)-benzylpenicillin,

D(-)-α-(3-cinnamoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1,2,5,6-tetrahydrobenzoyl]-3-methyl-ureido)-benzylpenicillin,or

D(-)-α-(3-hexahydrobenzoyl-3-methyl-ureido)-benzylpenicillin.

EXAMPLE 4 SodiumD,L-α-(3-benzoyl-3-methyl-ureido)-p-methylbenzylpenicillin:

This penicillin was prepared, as described in Examples 1 and 2, from 5.5parts by weight of D,L-α-(3-benzoyl-3-methyl-ureido)-p-tolyl-aceticacid, 3 parts by weight of tetramethyl-chloroformamidinium chloride and4.35 parts by weight of 6-aminopenicillanic acid.

Yield: 59%. β-Lactam content: 84%.

    ______________________________________                                                 C         H         N       S                                        Calculated:                                                                            54.5      5.3       9.7     7.9                                      Found:   54.9      5.9       9.5     (5.6)                                    ______________________________________                                    

NMR signals at τ=2.5 (5 H), 2.5-3.0 (4 H), 4.3-4.65 (3.0 H), 5.8 (1 H),6.9 (3 H), 7.7 (3 H) and 8.2-8.5 ppm (6 H).

Effectiveness in Animal Experiments: A and B.

EXAMPLE 5 SodiumD,L-(3-γ-chlorobutyryl-3methyl-ureido)-(2-thienyl)methylpenicillin:

This penicillin was prepared, in the manner described in Examples 1 and2, from 5.9 parts by weight ofD,L-(3-γ-chlorobutyryl-3-methyl-ureido)-(2-thienyl)-acetic acid, 3.5parts by weight of tetramethylchloroformamidinium chloride and 4.06parts by weight of 6-aminopenicillanic acid.

Yield: 64%. β-Lactam content: 95.5%. NMR signals at τ=2.5-3.2 (3 H), 4.1(1 H), 4.4 (2 H), 5.8 (1 H), 6.3 (2 H), 6.7 (3 H), 7.2 (2 H), 7.9 (2 H)and 8.4 ppm (6 H). Effectiveness in Animal Experiments: B.

EXAMPLE 6

If, in the procedure of Example 1, theD(-)-α-(3-acetyl-3-allyl-ureido)-phenylacetic acid used there isreplaced by:

0.02 mol of: α-(3-acetyl-3-methyl-ureido)-p-tolylacetic acid,

α-(3-acetyl-3-methyl-ureido)-p-chlorophenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-p-methylsulphenylphenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-p-methoxyphenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-o-chlorophenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-m-iodo-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-2,6-dichloro-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-2,6-dimethoxy-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-2,4-dibromo-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-m-methyl-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-2,6-dimethyl-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-2-chloro-6-fluoro-phenylacetic acid,

α-(3-acetyl-3-methyl-ureido)-2-thienyl-acetic acid, or

α-(3-acetyl-3-methyl-ureido)-3-thienyl-acetic acid,

the sodium salts of the following penicillins are obtained:

α-(3-acetyl-3-methyl-ureido)-p-methylbenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-p-chloro-benzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-p-methylsulphenyl-benzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-p-methoxybenzyl-penicillin,

α-(3-acetyl-3-methyl-ureido)-o-chlorobenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-m-iodobenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-2,6-dimethoxybenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-2,4-dibromobenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-m-methylbenzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-2,6-dimethyl-benzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-2-chloro-6-fluoro-benzylpenicillin,

α-(3-acetyl-3-methyl-ureido)-α-2-thienylmethylpenicillin or

α-(3-acetyl-3-methyl-ureido)-α-3-thienylmethylpenicillin.

EXAMPLE 7 SodiumD(-)-α-(3-methoxycarbonyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin:

1.35 parts by weight of tetramethylchloroformamidinium chloride weredissolved in 15 parts by volume of dichloromethane and cooled to 0°Cwhile excluding moisture. 2.4 parts by weight ofD(-)-α-(3-methoxycarbonyl-3-methyl-ureido)-2,6-dichlorophenylaceticacid, in a little methylene chloride, were added to this solution. Asolution of 1.04 parts by volume of triethylamine in 5 parts by volumeof dichloromethane was now added dropwise at -5°C over the course of 30minutes. After a further 40 minutes at -5°C, the mixture was combinedwith a solution of the triethylamine salt from 2.22 parts by weight of6-aminopenicillanic acid and 1.6 parts by volume of triethylamine in 25parts by volume of dichloromethane, cooled to -20°C. The mixture was nowstirred for 30 minutes at 0°C, with a further 0.4 part by volume oftriethylamine being added after 15 minutes. Thereafter, the mixture wasstirred for a further 30 minutes at room temperature and poured intowater, the aqueous layer was separated off at pH 6.5, and the sodiumsalt of the penicillin was isolated as described in Example 1.

Yield: 28%. β-Lactam content: 94%. NMR signals at τ = 2.6 (2.1 H), 2.7(0.9 H), 3.4 (0.7 H), 3.8 (0.3 H), 4.35-4.50 (2 H), 5.8 (1 H), 6.15 (3H), 6.8 (2.1 H), 6.85 (0.9 H) and 8.45 ppm (6 H).

EXAMPLE 8 SodiumL(+)-α-(3-methoxycarbonyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin:

This penicillin was prepared, in the manner described in Example 7, from3.1 parts by weight ofL(+)-α-(3-methoxycarbonyl-3-methyl-ureido)-2,6-dichlorophenylaceticacid, 1.74 parts by weight of tetramethylchloroformamidinium chlorideand 2.87 parts by weight of 6-aminopenicillanic acid.

Yield: 47% β-Lactam content: 92% NMR signals at τ = 2.6 (1.8 H), 2.7(1.2 H), 3.35 (0.6 H) 3.8 (0.4 H), 4.4 (2 H), 5.75 (1 H), 6.15 (3 H),6.8 (1.8 H), 6.85 (1.2 H), and 8.4 ppm (6 H).

EXAMPLE 9 SodiumD,L-α-(3-methoxycarbonyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin:

A solution of 5.0 parts by weight ofD,L-α-(3-methoxycarbonyl-3-methylureido)-2,6-dichlorophenylacetic acidin 10 parts by volume of acetone was added dropwise, at 0°C, to asuspension of 3.0 parts by weight of finely groundtetramethylchloroformamidinium chloride in 20 parts by volume of dryacetone. After 5 minutes, the mixture was cooled to -5°C and 2.1 partsby volume of triethylamine in 10 parts by volume of acetone were addeddropwise, slowly and uniformly, over the course of 30 minutes whilstexcluding moisture. The mixture was kept at 0°C for 1 hour, whilestirring, and thereafter the precipitate was filtered off without thesolution rising to above 0°C. The filtrate was now added, in severalportions, to a solution of 3.23 parts by weight of 6-aminopenicillanicacid in 25 parts by volume of 80% strength aqueous tetrahydrofurane(sufficient 2 N NaOH being added for solution just to occur [pH 8.2]),at 0°C, while keeping the pH value at between 7.5 and 8.0 by adding 2 NNaOH. The mixture was allowed to come to room temperature whilestirring, where it was stirred until no further addition of sodiumhydroxide solution was necessary for maintaining the pH value of 7.5 to8.0 (1 to 2 hours). Thereafter, the pH value was lowered to 6.5 with alittle dilute hydrochloric acid, 20 parts by volume of water were added,and the tetrahydrofurane was evaporated off in vacuo at roomtemperature. The aqueous solution which remained was extracted once with25 parts by volume of ether and covered with 50 parts by volume of a 1:1mixture of ethyl acetate and ether. The solution was acidified to pH 2.0with dilute hydrochloric acid while cooling with ice, and the organicphase was separated off. The latter was twice washed with 10 parts byvolume of water at a time, dried over MgSO₄ for 4 hours at 0°C, andfiltered. The sodium salt of the penicillin was precipitated by adding15 parts by volume of a 1 molar solution of sodium 2-ethyl-hexanoate inether containing methanol. The solvent was almost completely distilledfrom the mixture in vacuo at 0°C, the residue was taken up in theminimum possible amount of methanol, and the product was precipitated byadding ether. After standing for 1 hour at 0°C, it was filtered off,washed with ether containing methanol and subsequently dried for severaldays over P₂ O₅ in a vacuum desiccator.

Yield: 71%. β-Lactam content: 68%.

    ______________________________________                                                 C        H        Cl     N      S                                    Calculated:                                                                            41.3     4.2      12.2   9.6    5.5                                  Found:   41.1     5.0      14.0   9.0    4.9                                  ______________________________________                                    

Nmr signals at τ = 2.5 (1.95 H), 2.6 (1.05 H), 3.35 and 3.40 (0.65 H),3.8 (0.35 H), 4.45 (2 H), 5.8 (1 H), 6.2 (3 H), 6.75 (1.95 H), 6.8 (1.05H) and 8.4 ppm (6 H).

EXAMPLE 10 A. D(-)-α-(3-Methoxycarbonyl-3-methyl-ureido)-phenylaceticacid:

15.1 parts by weight of D(-)-C-phenylglycine were stirred for 15 minuteswith 20:2 parts by weight of triethylamine in 180 parts by volume of a3:1 mixture of dimethylsulphoxide and water. 15.2 parts by weight ofN-methoxy-carbonyl-N-methyl-carbamic acid chloride in 30 parts by volumeof dry acetone were now added dropwise within 30 minutes in such a waythat the temperature did not exceed 20°C. The mixture was stirred for afurther 2 hours, 200 parts by volume of water were then added and thewhole was acidified to pH 2 with dilute hydrochloric acid. Thereafterthe mixture was extracted 3 times with 120 parts by volume of ethylacetate at a time, and the organic phase was washed with 50 parts byvolume of water and dried over MgSO₄. After filtration, the solvent wasdistilled off in vacuo, the remnants of dimethylsulphoxide were strippedoff at 80°C and 0.1 mm Hg. The glassy oil, which was left in 73% yield,was pure methoxycarbonyl-methyl-ureidophenylacetic acid, according tothe NMR spectrum.

    ______________________________________                                                 C           H           N                                            Calculated:                                                                            54.0        5.3         10.5                                         Found:   54.9        5.6          9.6                                         ______________________________________                                    

NMR signals at τ = 0.4 (1 H), 2.4-2.8 (5 H), 4.65 (1 H), 6.2 (3 H) and6.9 ppm (3 H).

B. Sodium D(-)-α-(3-methoxycarbonyl-3-methyl-ureido-benzylpenicillin:

This penicillin was prepared as described in Example 7, from 5.3 partsby weight of D(-)-α-(3-methoxycarbonyl-3-methylureido)-phenylaceticacid, 3.4 parts by weight of tetramethyl chloroformamidinium chlorideand 4.0 parts by weight of 6-amino-penicillanic acid.

Yield: 63%. β-Lactam content: 69%. NMR signals at τ = 2.3-2.9 (5 H),4.45 (1 H), 4.5 and 4.55 (2 H), 5.8 (1 H), 6.2 (3 H), 6.85 (3 H) and8.45 ppm (6 H).

The Table which follows compares the anti-bacterial action of thisproduct (A) with that of the penicillin (B) prepared from ampicillin andN-methoxycarbonyl-N-methyl-carbamic acid chloride, and with the product(C) which was prepared according to the instructions of Example 27:

    Type of Bacterium Effectiveness [units/ml]                                                    (A)    (B)      (C)                                           ______________________________________                                        Escherichia coli 14                                                                             12.5     6.25     100                                       Escherichia coli 183/58                                                                         50       25       200                                       Pseudomonas aerug. Bonn                                                                         50       25       400                                       Pseudomonas aerug. Walter                                                                       50       25       400                                       Klebsiella K 10   200      200      400                                       Klebsiella 63     200      200      400                                       Staphylococcus aureus 133                                                                       1.56     1.56     6.25                                      ______________________________________                                    

EXAMPLE 11 A. D(-)-α-(3-Isopropoxycarbonyl-3-methyl-ureido)-phenylaceticacid:

15.1 parts by weight of D(-)-C-phenylglycine were dissolved in 250 partsby volume of 50% strength aqueous dioxane by adding sufficient dilutesodium hydroxide solution. Thereafter the pH value was lowered to 7.8with 2 N HCl, whereupon a part of the phenylglycine precipitated in afinely divided form. The mixture was cooled to 0°C and 18.0 parts byweight of N-isopropoxycarbonyl-N-methylcarbamic acid chloride in 30parts by volume of anhydrous dioxane were added dropwise over the courseof 30 minutes, the pH value of 7.5-8.0 being maintained by simultaneousaddition of 2 N sodium hydroxide solution. The mixture was subsequentlystirred at room temperature until no further addition of alkali wasnecessary for keeping the pH constant. 300 parts by volume of water werenow added and the solution was extracted once with 150 parts by volumeof ether. Thereafter it was acidified to pH = 2 with N NCl, and the oilwhich precipitated was taken up in several portions of ethyl acetate.The combined organic solutions were washed once with 100 parts by volumeof water and were dried for some hours over MgSO₄. After filtration,they were evaporated, and the oily residue was freed of dioxane to60-80°C and 0.1 mm Hg. The glassy product was obtained in 48% yield. Itwas completely pure, according to the NMR spectrum and the thin layerchromatogram.

    ______________________________________                                                 C           H           N                                            Calculated:                                                                            57.1        6.1         9.5                                          Found:   56.9        5.7         9.8                                          ______________________________________                                    

NMR signals at τ = 0.3 (1 H), +0.4 (1 H), 2.3-2.8 (5 H), 4.6 (1 H), 5.0(1 H), 6.9 (3 H) and 8.75 ppm (6 H).

B. The following α-ureido-arylacetic acids were prepared as described inExample 11A:

1. D(-)-α-(3-Acetyl-3-allyl-ureido)-phenylacetic acid from 8.1 parts byweight of N-acetyl-N-allylcarbamic acid chloride and 7.5 parts by weightof D(-)-C-phenylglycine.

Yield: 100%.

    ______________________________________                                                 C           H           N                                            Calculated:                                                                            60.8        5.9         10.1                                         Found:   60.3        6.1          9.8                                         ______________________________________                                    

NMR signals at τ = 0.0 (1 H), 2.6 (5 H), 3.75-4.5 (1 H), 4.6 (1 H),4.7-5.15 (2 H), 5.5-5.9 (2 H) and 7.7 ppm (3 H).

2. D(-)-α-(3-γ-Chlorobutyryl-3-methyl-ureido)-phenylacetic acid from 9.9parts by weight of N-γ-chlorobutyryl-N-methylcarbamic acid chloride and7.5 parts by weight of D(-)-C-phenyl-glycine.

Yield: 99%.

    ______________________________________                                                 C         H         Cl      N                                        Calculated:                                                                            53.8      5.5       11.3    9.0                                      Found:   53.9      5.8       10.8    9.4                                      ______________________________________                                    

NMR signals at τ = -0.1 (1 H), 2.6 (5 H), 4.6 (1 H), 6.3 (2 H), 6.8 (3H), 7.2 (2 H) and 7.9 ppm (2 H).

3. D,L-α-(3-Benzoyl-3-methyl-ureido)-4-tolylacetic acid from 3.2 partsby weight of N-benzoyl-N-methylcarbamic acid chloride and 3.8 parts byweight of D,L-C-(4-tolyl)-glycine.

Yield: 90%.

NMR signals at τ = 2.5 (5 H), 2.6 (2 H), 2.8 (2 H), 4.5 (1 H), 6.85 (3H) and 7.7 ppm (3 H).

4.D(-)-α-(3-Methoxycarbonyl-3-methyl-ureido)-2,6-dichlorophenylaceticacidfrom 1.75 parts by weight of N-acetyl-N-methyl-carbamic acid chlorideand 3.31 parts by weight of D(-)-C-(2,6-dichlorophenyl)-glycinehydrobromide. [we assume that the acid, which can be obtained from2,6-dichlorobenzyldehyde via the hydantoin in a manner which is initself known, and which after acylation of the amino group and splittingof the racemate with optically active bases, followed by removal of theacylating group, is obtained in a laevo-rotatory and a dextro-rotatoryform, belongs, by analogy to the known conditions in the case ofC-phenylglycine, to the D-series in the laevo-rotatory form, and to theL-series in the dextro-rotary form].

Yield: 90%. Melting point = 149°C, [α]_(D) = 28.1° NMR signals at τ =0.2 (1 H), 2.5 (3 H), 3.6 (1 H), 6.2 (3 H) and 6.9 ppm (3 H).

5.L(+)-α-(3-Methoxycarbonyl-3-methyl-ureido)-2,6-dichlorophenylaceticacidfrom 1.6 parts by weight of N-methoxycarbonyl-N-methylcarbamic acidchloride and 3.01 parts by weight of L(+)-C-(2,6-dichlorophenyl)-glycinehydrobromide.

Yield: 100%, [α]_(D) = + 29.3°NMR signals as indicated in Example 9.B.4.

6. D,L-α-(3,Methoxycarbonyl-3-methyl-ureido)-2,6-dichlorophenylaceticacid from 3.03 parts by weight of N-methoxycarbonyl-N-methyl-carbamicacid chloride and 4.4 parts by weight ofD,L-C-(2,6-dichlorophenyl)-glycine.

Yield: 78%. Melting point = 216°C. NMR signals as indicated in Example9.B.4.

7. D(-)-α-(3-n-Butoxycarbonyl-3-methyl-ureido)-phenylacetic acid from9.7 parts by weight of N-n-butoxycarbonyl-N-methylcarbamic acid chlorideand 7.1 parts by weight of D-C-phenylglycine.

Yield: 100%.

    ______________________________________                                                 C           H           N                                            Calculated:                                                                            58.4        6.5         9.1                                          Found:   58.6        6.9         9.5                                          ______________________________________                                    

NMR signals at τ = 0.5 (1 H), 2.6 (5 H), 4.65 (1 H), 5.8 (2 H), 6.9 (3H), 8.0-9.0 (4 H) and 9.05 ppm (3 H).

8. D,L-α-(3-Benzoyl-3-allyl-ureido)-4-methoxyphenyl-glycine from 4.5parts by weight of N-benzoyl-N-allyl-carbamic acid chloride and 3.6parts by weight of D,L-C-(4-methoxyphenyl)glycine.

Yield: 70%

NMR signals at τ = 0.6 (1 H), 2.5 (5 H), 2.5 (5 H), 2.7 (2 H), 3.0 (2H), 3.8-4.5 (1 H), 4.6-5.2 (3 H), 5.6-5.8 (2 H) and 6.2 ppm (3 H).

9. D(-)-α-(3-Acetyl-3-benzyl-ureido)-phenylacetic acid from 8.5 parts byweight of N-acetyl-N-benzyl-carbamic acid chloride and 6.0 parts byweight of D(-)-C-phenylglycine.

Yield: 92%. Melting point = 183°-185°C.

    ______________________________________                                                 C           H           N                                            Calculated:                                                                            66.3        5.6         8.6                                          Found:   66.3        5.7         8.6                                          ______________________________________                                    

NMR signals τ = -0.1 (1 H), 2.6 (5 H), 2.7 (5 H), 4.55 (1 H), 5.0 (2 H)and 7.8 ppm (3 H).

10. D,L-α-(3-Benzoyl-3-allyl-ureido)-2,6-dichlorophenylacetic acid from4.5 parts by weight of N-benzoyl-N-allyl-carbamic acid chloride and 4.4parts by weight of D,L-C-(2,6-dichlorophenyl)-glycine.

Yield: 97%.

    ______________________________________                                                 C         H         Cl      N                                        Calculated:                                                                            56.0      4.0       17.4    6.9                                      Found:   55.6      4.4       16.0    6.5                                      ______________________________________                                    

NMR signals at τ = 0 (1 H), 2.3-2.65 (8 H), 3.6 (1 H), 3.9-4.5 (1 H),4.8-5.3 (2 H) and 5.6-5.9 ppm (2 H).

11. D,L-α-(3-Acetyl-3-allyl-ureido)-2-thienylacetic acid from 3.2 partsby weight of N-acetyl-N-allylcarbamic acid chloride and 2.9 parts byweight of D,L-C-(2-thienyl)-glycine. Yield: 99%.

NMR signals at τ = 2.5-3.1 (3 H), 3.7-4.4 (1 H), 4.3 (1 H), 4.6-5.1 (2H), 5.5-5.7 (2 H) and 7.7 ppm (3 H).

12.D,L-α-(3-Dimethylaminocarbonyl-3-methyl-ureido)-2,6-dichloro-phenylaceticacid from 3.3 parts by weight ofN-dimethylamino-carbonyl-N-methyl-carbamic acid chloride and 4.4 partsby weight of D,L-C-(2,6-dichlorophenyl)-glycine.

Yield: 86%. Melting point = 205°C. NMR signals at τ = 1.6 (1 H), 2.5 (3H), 3.7 (1 H), 7.0 (3 H) and 7.1 ppm (6 H).

13. D,L-α-(3-Methoxycarbonyl-3-methyl-ureido)-4-methoxyphenylacetic acidfrom 3.0 parts by weight of N-methoxycarbonyl-N-methylcarbamic acidchloride and 3.6 parts by weight of D,L-C-(4-methoxyphenyl)-glycine.

Yield: 87%. NMR signals at τ = 2.6 (2 H), 3.05 (2 H), 4.6 (1 H), 6.2 (6H) and 6.8 ppm (3 H).

14.D,L-α-(3-Dimethylaminocarbonyl-3-methyl-ureido)-4-methoxyphenylaceticacid from 3.3 parts by weight ofN-dimethylaminocarbonyl-N-methylcarbamic acid chloride and 3.6 parts byweight of D,L-C-(4-methoxyphenyl)-glycine.

Yield: 100%. NMR signals at τ = 2.0 (1 H), 2.6 (2 H), 3.05 (2 H), 4.6 (1H), 6.2 (3 H), 6.95 (3 H) and 7.1 ppm (6 H).

15. D,L-α-(3-Methoxycarbonyl-3-methyl-ureido)-2-thienyl acetic acid from3.0 parts by weight of N-methoxycarbonyl-N-methylcarbamic acidhydrochloride and 2.9 parts by weight of D,L-C-(2-thienyl)-glycine.

Yield: 100%. NMR signals at τ = 0.4 (1 H), 2.5-3.1 (3 H), 4.25 (1 H),6.2 (3 H) and 6.8 ppm (3 H).

16. D,L-α-(3-Dimethylaminocarbonyl-3-methyl-ureido-phenylacetic acidfrom 3.3 parts by weight of N-dimethylaminocarbonyl-3-methyl-carbamicacid chloride and 2.9 parts by weight of D,L-C-(2-thienyl)-glycine.

Yield: 84%. NMR signals at τ = 1.9 (1 H), 2.5-3.1 (3 H), 4.3 (1 H), 6.9(3 H) and 7.1 ppm (6 H)

17. D,L-α-(3-Benzoyl-3-allyl-ureido)-α-2-thienylacetic acid from 4.5parts by weight of N-benzoyl-N-allyl-carbamic acid chloride and 2.9parts by weight of D,L-C-(2-thienyl)-glycine.

Yield: 96%. NMR signals at τ = 2.5 (5 H), 2.5-3.1 (3 H), 3.8-4.5 (2 H),4.8-5.3 (2 H) and 5.5-5.8 ppm (2 H).

18. D,L-α-(3γ-Chlorobutyryl-3-methyl-ureido)-2-thienylacetic acid from4.0 parts by weight of N-γ-chlorobutyryl-N-methylcarbamic acid chlorideand 2.9 parts by weight of D,L-α-(2-thienyl)-glycine.

Yield: 99%. NMR signals at τ = 2.5-3.1 (3 H), 4.2 (1 H), 6.35 (2 H), 6.7(3 H), 7.2 (2 H), and 7.9 ppm (2 H).

19. D,L-α-(3-[2-Furoyl]-3-methyl-ureido)-2-thienylacetic acid from 5.6parts by weight of N-(2-furoyl)-N-methyl-carbamic acid chloride and 4.7parts by weight of D,L-C-(2-thienyl)-glycine.

Yield: 100%.

20. D(-)-α-(3-Allyloxycarbonyl-3-methyl-ureido)-phenylacetic acid from15.8 parts by weight of N-allyoxycarbonyl-N-methylcarbamic acid chlorideand 15.1 parts by weight of D-C-phenylglycine.

Yield: 88%. NMR signals at τ = -1.8 (1 H), +0.4 (1 H), 2.6 (5 H),3.7-4.3 (1 H), 4.4-4.9 (3 H), 5.3 (2 H), and 6.85 ppm (3 H).

21. D(-)-α-(3-[3-Nitro-4-methylbenzoyl]-3-methyl-ureido)-phenylaceticacid from 8.0 parts by weight ofN-(3-nitro-4-methylbenzoyl)-N-methyl-carbamic acid chloride and 4.7parts by weight of D(-)-C-phenylgycine.

Yield: 46%. NMR signals at τ = 1.6-2.8 (8 H), 4.6 (1 H), 6.8 (3 H) and7.4 ppm (3 H).

22. D(-)-α-(3-[4-Methylbenzoyl]-3-methyl-ureido)-phenylacetic acid from13 parts by weight of N-p-methylbenzoyl-N-methylcarbamic acid chlorideand 9.2 parts by weight of D(-)-C-phenylglycine.

Yield: 85%. NMR signals at τ = 0.2 (1 H), 2.4-2.9 (9 H), 6.65 (1 H), 6.9(3 H) and 7.6 ppm (3 H).

23. D,L-α-(3-Benzoyl-3-methyl-ureido)-2,6-dichlorophenylacetic acid from7.2 parts by weight of N-benzoyl-N-methylcarbamic acid chloride and 8.0parts by weight of D,L-C-(2,6-dichlorophenyl)-glycine.

Yield: 100%. Melting point = 200°C. NMR signals at τ = -0.4 (1 H),2.2-2.7 (8 H), 3.5 (1 H) and 6.9 (3 H).

24. D,L-α-(3-Benzoyl-3-methyl-ureido)-4-methylsulphenylphenylacetic acidfrom 10.0 parts by weight of N-benzoyl-N-methylcarbamic acid chlorideand 10.0 parts by weight of D,L-C-(4-methylsulphenylphenyl)-glycine.

Yield: 73%. NMR signals at τ = 0.2 (1 H), 2.3-2.8 (9 H), 4.65 (1 H), 6.9(3 H) and 7.5 ppm (3 H).

25.D,L-α-(3-Ethoxycarbonyl-3-methyl-ureido)-4-methylsulphenylphenylaceticacid from 16.8 parts by weight of N-ethoxycarbonyl-N-methyl-carbamicacid chloride and 20.0 parts by weight ofD,L-C-(4-methylsulphenylphenyl)-glycine. NMR signals at τ = 0.4 (1 H),2.4-2.9 (4 H), 4.65 (1 H), 5.75 (2 H), 6.85 (3 H) and 7.55 ppm (3 H).

26.D,L-α-(3-β-Chloropropionyl-3-methylureido)-(1,2,5,6-tetrahydrophenylaceticacid from 18.4 parts by weight of N-β-chloropropionyl-N-methylcarbamicacid chloride and 15.5 parts by weight ofD,L-C-(1,2,5,6-tetrahydrophenyl)-glycine.

Yield: 73%. NMR signals at τ = 0.6 (1 H), 4.3 (2 H), 5.7 (1 H), 6.2 (2H), 6.8 (2 H) and 7.7-8.8 ppm (7 H).

27. D(-)-α-(3-[2 -Thenoyl]-3-methyl-ureido)-phenylacetic acid from 9.0parts by weight of N-(2-thenoyl)-N-methyl-carbamic acid chloride and 6.6parts by weight of D-C-phenylglycine.

Yield: 50%.

28. D(-)-α-(3,5-Dimethyl-isoxazol-4-oyl]-3-methyl-ureido)-phenylaceticacid from 8.5 parts by weight ofN-(3,5-dimethylisoxazol-4-oyl)-N-methylcarbamic acid chloride and 5.9parts by weight of D-C-phenylglycine.

Yield: 32%.

C. SodiumD(-)-α-(3-isopropoxycarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was manufactured as described in Example 9 from 5.9parts by weight ofD(-)-α-(3-isopropoxycarbonyl-3-methyl-ureido)-phenylacetic acid, 3.7parts by weight of tetramethylchloroformamidinium chloride and 4.0 partsby weight of 6-aminopenicillanic acid.

Yield: 45%. β-Lactam content: 86%

    ______________________________________                                                 C         H         N       S                                        Calculated:                                                                            48.8      5.6       10.4    5.9                                      Found:   48.7      5.9       10.8    5.8                                      ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.4 (1 H), 4.55 (2 H), 5.0 (1 H), 5.8(1 H), 6.85 (3 H), 8.5 (6 H), and 8.7 ppm (6 H).

The Table which follows compares the anti-bacterial action of thisproduct (A) with the penicillin (B) prepared from ampicillin andN-i-propoxycarbonyl-N-methylcarbamic acid chloride and with the product(C) which was obtained fromD(-)-α-(3-i-propoxycarbonyl-3-methylureido)-phenylacetic acid accordingto the procedure described in Example 28:

    Type of Bacterium                                                                             Effectiveness [units/ml]                                                    (A)     (B)       (C)                                           ______________________________________                                        Escherichia coli 14                                                                           6.25      6.25      100                                       Escherichia coli C 165                                                                        50        25        200                                       Escherichia coli 183/58                                                                       12.5      6.25      400                                       Pseudomonas aer. Bonn.                                                                        50        25        >400                                      Pseudomonas aer. Walter                                                                       100       50        >400                                      ______________________________________                                    

EXAMPLE 12 SodiumD(-)-α-(3-n-butoxycarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared in the manner described in Example 9 from5.6 parts by weight ofD(-)-α-(3-n-butoxycarbonyl-3-methyl-ureido)-phenylacetic acid, 3.3 partsby weight of tetramethyl-chloroformamidinium chloride and 3.6 parts byweight of 6-aminopenicillanic acid. The ureidoacetic acid was stirredwith the tetramethylchloroformamidinium chloride in acetone at -5°C foronly 20 minutes.

Yield: 38%. β-Lactam content: 61%.

    ______________________________________                                                 C         H         N       S                                        Calculated:                                                                            48.1      6.0       9.7     5.6                                      Found:   48.4      5.5       9.4     5.5                                      ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.4 (1 H), 4.55 (2 H), 5.8 (3 H), 6.85(3 H) and 8.1-8.9 ppm (13 H).

EXAMPLE 13

If, in the procedure of Example 10, theD(-)-α-(3-methoxycarbonyl-3-methyl-ureido)-phenylacetic acid used thereis replaced by 0.018 mol of:

D(-)-α-(3-ethoxycarbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-i-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-n-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-allyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-cyclohexyl-ureido)-phenylacetic acid,

D(-)-α-(3-dimethylaminocarbonyl-3-phenyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1-pyrrolidylcarbonyl]-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1-piperidylcarbonyl]-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-diethylaminocarbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-ethylaminocarbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-methylaminocarbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-phenylaminocarbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[4-morpholinyl]-carbonyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1-pyrrolidylcarbonyl]-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1-piperidylcarbonyl]-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-diethylaminocarbonyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-ethylaminocarbonyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-methylaminocarbonyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-phenylaminocarbonyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-[4-morpholinyl]-carbonyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1-pyrrolidyl]-carbonyl-3-n-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-[1-piperidyl]-carbonyl-3-i-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-diethylaminocarbonyl)-3-n-butyl-ureido)-phenylacetic acid or

D(-)-α-(3-dimethylaminocarbonyl)-3-cyclohexyl-ureido-phenylacetic acid,the sodium salts of the following penicillins are obtained:

D(-)-α-(3-ethoxycarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-i-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-n-butyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-allyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-cyclohexyl-ureido)-benzylpenicillin

D(-)-α-(3-dimethylaminocarbonyl-3-phenyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-pyrrolidylcarbonyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-piperidylcarbonyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-diethylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-ethylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-methylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-phenylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[4-morpholinyl]-carbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-pyrrolidylcarbonyl]-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-piperidylcarbonyl]-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-diethylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-ethylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-methylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-phenylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-[4-morpholinyl]-carbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-pyrrolidyl]-carbonyl-3-n-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-piperidyl]-carbonyl-3-i-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-diethylaminocarbonyl)-3-n-butyl-ureido)-benzylpencillin, or

D(-)-α-(3-diethylaminocarbonyl)-3-cyclohexyl-ureido)-benzylpenicillin

EXAMPLE 14 SodiumD,L-α-(3-benzoyl-3-allyl-ureido)-4-methoxybenzylpenicillin:

This penicillin was prepared in the manner described in Example 9, from4.4 parts by weight ofD,L-α-(3-benzoyl-3-allyl-ureido)-4-methoxyphenylacetic acid, 2.26 partsby weight of tetramethylchloroformamidinium chloride and 2.6 parts byweight of 6-aminopenicillanic acid.

Yield: 51%. β-Lactam content: 65%.

    ______________________________________                                                 C         H         N       S                                        Calculated:                                                                            55.4      5.2       9.2     5.3                                      Found:   55.4      4.8       8.1     4.5                                      ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 2.7 (2 H), 3.2 (2 H), 3.9-4.5 (1 H), 4.55(3 H), 4.7-5.2 (2 H), 5.6-5.9 (3 H), 6.25 (3 H) and 8.4 ppm (6 H).

EXAMPLE 15 SodiumD,L-α-(3-benzoyl-3-allyl-ureido)-2,6-dichlorobenzylpenicillin:

This penicillin was prepared in the manner described in Example 9 from7.2 parts by weight ofD,L-α-(3-benzoyl-3-allyl-ureido)-2,6-dichlorophenylacetic acid, 4.05parts by weight of tetramethylchloroformamidinium chloride and 3.86parts by weight of 6-aminopenicillanic acid.

Yield: 46%. β-Lactam content: 83%.

    ______________________________________                                                 C        H        Cl     N      S                                    Calculated:                                                                            49.5     4.3      10.8   8.6    4.9                                  Found:   49.9     5.1      11.3   8.2    4.4                                  ______________________________________                                    

NMR signals at τ = 2.4-2.9 (8 H), 3.4 (1 H), 3.8-4.4 (1 H), 4.4-4.6 (2H), 4.8-5.2 (2 H), 5.5-5.8 (2 H), 5.85 (1 H) and 8.5 ppm (6 H).

EXAMPLE 16

If, in the procedure of Example 4, theD,L-α-(3-benzoyl-3-methyl-ureido)-p-tolyl-acetic acid used there isreplaced by 0.015 mol of:

D(-)-α-(3-benzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-benzoyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-4-chlorophenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-4-methoxyphenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2-chlorophenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-3-iodophenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2,6-dimethoxyphenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2,4-dibromophenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-3-thienylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-m-tolylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2,6-dimethylphenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2-chloro-6-fluorophenylacetic acid,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2-thienylacetic acid,

L(+)-α-(3-benzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[3-nitro-4-methoxyphenyl]-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-p-chlorobenzoyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-o-bromobenzoyl-3-n-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-methoxybenzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-p-methoxycarbonylaminobenzoyl-3-methyl-ureido)-phenylaceticacid,

D(-)-α-(3-p-methylsulphenylbenzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[2-chloro-5-methoxybenzoyl]-3-n-butyl-ureido)-phenylaceticacid,

D(-)-α-(3-p-nitrobenzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[2-chloro-4-ethylsulphenylbenzoyl]-3-methyl-ureido)-phenylaceticacid,

D(-)-α-(3-m-cyanobenzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-[3,5-dimethylbenzoyl]-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-benzoyl-3-allyl-ureido)-phenylacetic acid,

D(-)-α-(3-m-iodobenzoyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-benzoyl-3-phenyl-ureido)-phenylacetic acid or

D(-)-α-(3-naphthoyl(1)-3-methyl-ureido)-phenylacetic acid,

the sodium salts of the following penicillins are obtained:

D(-)-α-(3-benzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-benzoyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-4-chlorobenzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-4-methoxybenzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2-chloro-benzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-3-iodo-benzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2,6-dimethoxy-benzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2,4-dibromo-benzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-3-thienylmethylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-3-methylbenzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2,6-dimethylbenzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2-chloro-6-fluorobenzylpenicillin,

D(-)-α-(3-benzoyl-3-methyl-ureido)-2-thienylmethylpenicillin,

L(+)-α-(3-benzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[3-nitro-4-methoxyphenyl]-3-methyl-ureido)-benzylpenicillin

D(-)-α-(3-p-methoxybenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-methoxycarbonylaminobenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-chlorobenzoyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-o-bromobenzoyl-3-n-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-[2-chloro-5-methoxybenzoyl]-3-n-butyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-methylsulphenylbenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-nitrobenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[2-chloro-4-ethylsulphenyl-benzoyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-m-cyano-benzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[3,5-dimethyl-benzoyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-benzoyl-3-allyl-ureido)-benzylpenicillin,

D(-)-α-(3-m-iodobenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-benzoyl-3-phenyl-ureido)-benzylpenicillin or

D(-)-α-(3-naphthyl(1)-3-methyl-ureido)-benzylpenicillin.

EXAMPLE 17. SodiumD,L-α-(3-acetyl-3-allyl-ureido)-2-thienylmethylpenicillin:

This penicillin was prepared in the manner described in Example 9 from5.0 parts by weight of D,L-α-(3-acetyl-3-allyl-ureido)-2-thienyl-aceticacid, 3.6 parts by weight of tetramethylchloroformamidinium chloride and3.9 parts by weight of 6-aminopenicillanic acid.

Yield: 53%. β-Lactam content: 72%.

    ______________________________________                                                 C         H         N       S                                        Calculated:                                                                            46.2      4.9       10.8    12.3                                     Found:   46.6      5.3       10.4    12.3                                     ______________________________________                                    

NMR signals at τ = 2.5-3.2 (3 H), 3.8-4.4 (1 H), 4.2 (1 H), 4.5 (2 H),4.6-5.0 (2 H), 5.5-5.7 (2 H), 5.8 (1 H), 7.7 (3 H) and 8.4 ppm (6 H).

EXAMPLE 18 SodiumD,L-α-(3-methoxycarbonyl-3-methyl-ureido)-4-methoxybenzylpenicillin:

3.04 parts by weight of tetramethylchloroformamidinium chloride in 20parts by volume of dry dichloromethane were intially taken at 0°C, and asolution of 4.8 parts by weight ofD,L-α-(3-methoxycarbonyl-3-methylureido)-4-methoxyphenylacetic acid in10 parts by volume of methylene chloride was added. 2.24 parts by volumeof triethylamine in 10 parts by volume of methylene chloride were nowadded dropwise over the course of 30 minutes at 0°C, with exclusion ofmoisture. Thereafter the mixture was stirred for 20 minutes at +5°C,insoluble matter was filtered off without the solution rising to above5°C, and the filtrate was cooled to -20°C. A solution of 5.0 parts byweight of 6-aminopenicillanic acid and 3.5 parts by volume oftriethylamine in 20 parts by volume of methylene chloride, prepared asdescribed in Example 1, and also cooled to -20°C, was added thereto. Themixture was stirred for 30 minutes at 0°C and subsequently for a further30 minutes at room temperature, and was finally poured into 150 parts byvolume of ice water and adjusted to a pH value of 6.5 with 2 N sodiumhydroxide solution. After separating off the organic layer and adding150 parts by volume of a 1:1 mixture of ethyl acetate and ether, themixture was worked up as described in Example 1 and the sodium salt ofthe penicillin was isolated.

Yield: 54%. β-Lactam content: 75%. NMR signals at τ = 2.6 (2 H), 3.1 (2H), 4.3-4.9 (3 H), 5.8 (1 H), 6.2 (6 H), 6.85 (3 H) and 8.5 ppm (6 H).

Effectiveness in Animal Experiments: B.

EXAMPLE 19 SodiumD,L-α-(3-dimethylaminocarbonyl-3-methyl-ureido)-4-methoxybenzylpenicillin:

This penicillin was prepared as described in Example 18, from 6.0 partsby weight ofD,L-α-(3-dimethyl-aminocarbonyl-3-methyl-ureido)-4-methoxyphenylaceticacid, 3.8 parts by weight of tetramethylchloroformamidinium chloride and6.2 parts by weight of 6-aminopenicillanic acid.

Yield: 23%. β-Lactam content: 59%. NMR signals at τ = 2.65 (2 H), 3.1 (2H), 4.4-4.8 (3 H), 5.65 (1 H), 6.2 (3 H), 6.9 (3 H), 7.05 (6 H) and 8.4ppm (6 H).

EXAMPLE 20 SodiumD,L-α-(3-methoxycarbonyl-3-methyl-ureido)-2-thienylmethylpenicillin:

This penicillin was prepared as described in Example 18, from 4.5 partsby weight of D,L-α-(3-methoxycarbonyl-3-methyl-ureido)-thienylaceticacid, 3.2 parts by weight of tetramethylchloroformamidinium chloride and5.2 parts by weight of 6-aminopenicillanic acid.

Yield 62%. β-Lactam content: 84%. NMR signals at τ = 2.5-3.2 (3 H), 4.2(1 H), 4.5 (2 H), 5.8 (1 H), 6.2 (3 H), 6.8 (3 H) and 8.4 ppm (6 H).

Effectiveness in animal experiments: A

EXAMPLE 21 SodiumD,L-α-(3-benzoyl-3-allyl-ureido)-2-thienylmethylpenicillin:

This penicillin was prepared as described in Example 18, from 6.0 partsby weight of D,L-α-(3-benzoyl-3-allyl-ureido) -2-thienylacetic acid, 3.4parts by weight of tetramethylchloroformamidinium chloride and 5.5 partsby weight of 6-aminopenicillanic acid.

Yield: 45%. β-Lactam content: 77%. NMR signals at τ = 2.5 (5 H), 2.5-3.1(3 H), 3.7-4.4 (2 H), 4.5 (2 H), 4.7-5.2 (2 H), 5.5-5.9 (3 H) and 8.4ppm (6 H).

Effectiveness in Animal Experiments: B.

EXAMPLE 22 SodiumD,L-α-(3-[2-furoyl]-3-methyl-ureido)-2-thienylmethylpenicillin:

This penicillin was prepared as described in Example 18, from 11.6 partsby weight of D,L-α-(3-[2-furoyl]-3-methyl-ureido)2-thienylacetic acid,6.5 parts by weight of tetramethylchloroform-amidinium chloride and 3.2parts by weight of 6-aminopenicillanic acid.

Yield: 39%. β-Lactam content: 88%. NMR signals at τ = 2.2 (1 H), 2.5-3.1(4 H), 3.35 (1 H), 4.1 (1 H), 4.45 (2 H), 5.8 (1 H), 6.55 (3 H) and 8.4ppm (6 H).

Effectiveness in animal experiments: A and B

EXAMPLE 23 SodiumD,L-α-(3-dimethylaminocarbonyl-3-methyl-ureido)-2-thienylmethylpenicillin:

A suspension of 3.9 parts by weight of tetramethylchloroformamidiniumchloride in 30 parts by volume of dry acetone was treated with asolution ofD,L-α-(3-dimethylaminocarbonyl-3-methyl-ureido)2-thienylacetic acid in10 parts by volume of acetone over the course of 5 minutes at -20°C, andsubsequently 2.1 parts by volume of triethylamine in 5 parts by volumeof acetone were added dropwise over the course of 30 minutes. After themixture had been stirred for a further hour at -20°C, it was filtered insuch a way that the temperature of the solution did not rise above-10°C. It was again cooled to -20°C and combined with a vigorouslystirred solution of 3.9 parts by weight of 6-aminopenicillanic acid in50 ml of 60% strength aqueous tetrahydrofurane (solution took placeafter adding sufficient 2 N NaOH to establish a pH value of 8.2), cooledto -5°C. A pH range of 7.5 - 8.0 was maintained by adding 2 N sodiumhydroxide solution. After 15 minutes, the mixture was allowed to come toroom temperature and stirring was continued until no further change inthe pH value was observable. The subsequent working-up of the reactionmixture and the isolation of the penicillin was carried out in themanner indicated in Example 9.

Yield: 43%. β-Lactam content: 54%. NMR signals at τ = 2.5-3.2 (3 H), 4.5(3 H), 5.8 (1 H), 6.9 (3 H), 7.05 (6 H), and 8.4 ppm (6 H).

EXAMPLE 24 SodiumD(-)-α-(3-γ-chlorobutyryl-3-methyl-ureido)-benzylpenicillin:

5.1 parts by weight ofD(-)-α-(3-γ-chlorobutyryl-3-methyl-ureido)-phenylacetic acid and 3.0parts by weight of tetramethylchloro-formamidinium chloride were reactedin methylene chloride as described in Example 18. The resulting solutionwas combined with a solution of 6.5 parts by weight ofN-trimethylsilyl-6-aminopenicillanic acid trimethylsilyl ester in 33parts by volume of dry methylene chloride at 0°C. 1.3 parts by weight ofpyridine were added and the mixture was stirred, while excludingmoisture, for 1 hour at 0°C and subsequently for 2.5 hours at roomtemperature. It was now poured into 120 parts by volume of ice water, apH value of 7 - 8 was established and the methylene chloride wasstripped off in vacuo. The aqueous phase was shaken with 50 parts byvolume of ether, which was then discarded, whilst the aqueous phase wasfreed of solid constituents by filtration. It was now covered with 200parts by volume of a 1 : 1 mixture of ether and ethyl acetate, cooled to0°C and acidified to pH = 2 with 2 N hydrochloric acid, while stirringvigorously. The organic solution was separated off, twice washed with 50parts by volume of water at a time, dried over MgSO₄ and filtered, andthe sodium salt of the penicillin was precipitated by adding 15 ml of a1 M solution of sodium 2-ethylhexanoate in ether containing methanol.The entire mixture was concentrated almost to dryness at 0°C, rapidlydissolved in as little methanol as possible, and precipitated by addingexcess ether. Non-crystalline solid substance.

Yield: 29% β-Lactam content: 49%.

Position of the NMR signals as indicated in Example 2.

The crude product still containedD-α-(3-γ-chlorobutyryl-3-methyl-ureido)-phenylacetic acid which wasremovable by fractional extraction of the aqueous penicillin saltsolution at pH values of 5.5 - 6.5.

EXAMPLE 25

If, in the procedure of Example 1, theD(-)-α-(3-acetyl-3-allyl-ureido)-phenylacetic acid used there isreplaced by 0.02 mol of:

D(-)-α-(3-acetyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-vinyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-n-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-propenyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-i-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-n-butyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-β-methoxyethyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-β-dimethylaminoethyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-cyclohexyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-cyclobutyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-benzyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-i-propyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-t-butyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-n-butyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-allyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-benzyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-phenyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-cyclopropyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-cyclobutyl-ureido)-phenylacetic acid,

D(-)-α-(3-formyl-3-cyclopentyl-ureido)-phenylacetic acid or

D(-)-α-(3-formyl-3-cyclohexyl-ureido)-phenylacetic acid,

the following penicillins are obtained in the form of their sodiumsalts:-

D(-)-α-(3-acetyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-vinyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-n-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-prop-1-enyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-i-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-n-butyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3t-butyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-β-methoxyethyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-β-dimethylaminoethyl-ureido)-benzylpenicillin

D(-)-α-(3-acetyl-3-cyclohexyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-cyclobutyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-benzyl-uriedo)-benzylpenicillin,

D(-)-α-(3-formyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-i-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-n-butyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-allyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-benzyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-phenyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-cyclopropyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-cyclobutyl-ureido)-benzylpenicillin,

D(-)-α-(3-formyl-3-cyclopentyl-ureido)-benzylpenicillin, or

D(-)-α-(3-formyl-3-cyclohexyl-ureido)-benzylpenicillin.

EXAMPLE 26

If, in the procedure of Example 1, theD(-)-α-(3-acetyl-3-allyl-ureido)-phenylacetic acid used there isreplaced by 0.02 mol of:

D(-)-α-(3-methoxyacetyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-propionyl-3-methyl-ureido-phenylacetic acid,

D(-)-α-(3-methylsulphenylacetyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-propionyl-3-ethyl-ureido)-phenylacetic acid,

D(-)-α-(3-propionyl-3-vinyl-ureido)-phenylacetic acid,

D(-)-α-(3-n-butyryl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-methoxycarbonyl-acetyl-3-methyl-ureido)-phenylacetic acid.

D(-)-α-(3-i-butyryl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-acryloyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-pivaloyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-cyanomethyl-acetyl-3-methyl-ureido)-phenylacetic acid,

D(-)-α-(3-acetyl-3-phenyl-ureido)-phenylacetic acid,

D(-)-α-(3-propionyl-3-phenyl-ureido)-phenylacetic acid,D(-)-α-(hexahydroazepin-2-on-1-yl-carbonylamino)-phenylacetic acid, orD(-)-α-(pyrrolid-2-on-1-yl-carbonylamino)-phenylacetic acid,

the following penicillins are obtained:

D(-)-α-(3-methoxyacetyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-propionyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-methylsulphenylacetyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-propionyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-propionyl-3-vinyl-ureido)-benzylpenicillin,

D(-)-α-(3-n-butyryl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-methoxycarbonylacetyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-i-butyryl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-acryloyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-pivaloyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-cyanomethyl-acetyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-acetyl-3-phenyl-ureido)-benzylpenicillin,

D(-)-α-(3-propionyl-3-phenyl-ureido)-benzylpenicillin,

D(-)-α-(hexahydroazepin-2-on-1-yl-carbonylamino)-benzylpenicillin or

D(-)-α-(pyrrolid-2-on-1-yl-carbonylamino)-benzylpenicillin.

EXAMPLE 27 Attempt to prepare sodiumD(-)-α-(3-methexycarbonyl-3-methylureido)-benzylpenicillin:

5.2 parts by weight ofD(-)-α-(3-methoxycarbonyl-3-methylureido)-phenylacetic acid weresuspended in a mixture of 10 parts by weight of benzene, 5 parts byweight of thionyl chloride and 0.05 part by weight of dimethylformamideand the mixture was subsequently carefully warmed, whilst stirring witha magnetic stirrer. The mixture was kept at about 60°C until theevolution of gas had ceased, and subsequently thionyl chloride andbenzene were removed in a waterpump vacuum, finally at 0.1 mm Hg and50°C. The product which remained showed strong bands in the IR spectrumat 1805, 1725 and 1175 cm⁻ ¹.

Yield: 5.5 parts by weight. Calculated asD(-)-α-(3-methoxycarbonyl-3-methyl-ureido)-phenylacetic acid chloride:

    Calculated:                                                                            C 50.55   H 4.56    Cl 12.47 N 9.84                                  Found:   C 47.57   H 4.29    Cl 11.6  N 9.68                              

5 parts by weight of the product thus obtained, dissolved in 10 parts byvolume of dry tetrahydrofurane, were added dropwise, while stirring, toan ice-cooled solution of 3.8 parts by weight of 6-aminopenicillanicacid in 50 parts by volume of 80% strength aqueous tetrahydrofurane(addition of sufficient 2 N sodium hydroxide solution for solution tooccur at pH 8.2). In the course thereof, the pH value was kept atbetween 7 and 8 by simultaneous addition of further 2 N sodium hydroxidesolution. Thereafter, the mixture was further stirred for 30 minutes at0°C and then stirred at room temperature until no further addition ofsodium hydroxide solution was necessary for maintaining a pH value of7 - 8.

100 parts by volume of water were now added, the tetrahydrofurane wasremoved at 0°C in vacuo, and the aqueous solution which remained wasextracted with 50 parts by volume of ether to remove neutralconstituents. It was then covered with 150 parts by volume of a 1 : 1mixture of ether and ethyl acetate and thereafter acidified with dilutehydrochloric acid to pH = 2.0, while cooling with ice and stirring.

The organic phase was separated off, washed with 50 parts by volume ofwater and dried over MgSO₄.

Thereafter, 17 parts by volume of a 1 M solution of sodium2-ethylhexanoate in ether containing methanol were added, the mixturewas evaporated almost to dryness in vacuo, and the residue was dissolvedin the minimum amount of methanol. On adding excess ether, a colorless,non-crystalline product precipitated, which, after decanting thesupernatant solution, was digested with ether, filtered off and driedover P₂ O₅ in a vacuum desiccator.

Yield: 6 parts by weight. β-Lactam content: 88%. Calculated asmethoxycarbonyl-methyl-ureido- benzylpenicillin:

          C 49.3   H 4.7    Cl --  N 11.5  S 6.6                                  Found:                                                                              C 47.5   H 6.0    Cl 0.1 N  9.9  S 7.0                              

The thin layer chromatogram of the product (silica gel, 10 : 3 : 1mixture of n-butanol, n-pentane and glacial acetic acid, running time1.5 hours) showed spots at Rf values of 0.045, 0.11 - 0.3 and 0.56.Authentic D(-)-α-(3-methoxycarbonyl-3-methyl-ureido)-benzylpenicillin,manufactured either according to the method of Example 8 or by acylationof ampicillin with N-methoxycarbonyl-N-methyl-carbamic acid chloride,showed an Rf value of 0.45 under the same conditions. Anelectrophorogram developed with Bacillus subtilis showed the presence ofseveral antibiotically active substances, of which, however, none agreedwith the authentic material. Finally, the NMR spectrum permitted thepresence of major amounts of the desiredmethoxycarbonyl-methylureido-benzylpenicillin to be ruled out; rather,it confirmed the assumption of a mixture of several differentsubstances.

As regards the anti-bacterial effectiveness of this product, see theTable accompanying Example 8.

EXAMPLE 28

In the reaction ofD(-)-α(3-i-propoxycarbonyl-3-methylureido)-phenylacetic acid and ofD(-)-α-(3-n-butoxycarbonyl-3-methyl-ureido)-phenylacetic acid withthionyl chloride and subsequently with 6-aminopenicillanic acid in themanner described in Example 11 C, products were in each case againobtained which proved to be mixtures of several antibiotically activesubstances, but of which none was identical with the authenticD(-)-α-(3-i-propoxycarbonyl-3-methyl-ureido)-benzylpenicillin orD(-)-α-(3-n-butoxycarbonyl-3-methyl-ureido)-benzylpenicillinmanufactured according to the instruction of Examples 9C and 10. The Rfvalues of thin layer chromatograms developed on silica gel with a 9 : 3: 1 mixture of n-butanol, pentane and glacial acetic acid were 0.080 and0.35, and 0.078, 0.46 and 0.75, respectively.

Under the same conditions, the authentic products showed Rf values of0.56 and 0.64 respectively.

Products from the reaction ofD(-)-α-(3-i-propoxycarbonyl-3-methyl-ureido)-phenylacetic acid:

For anti-bacterial effectiveness, see the Table accompanying Example 9C.

Products from the reaction ofD(-)-α-(3-n-butoxycarbonyl-3-methyl-ureido)-phenylacetic acid:

The Table which follows compares the anti-bacterial action of thisproduct (A) with the penicillins (B) prepared from ampicillin andN-n-butoxycarbonyl-N-methyl-carbamic acid chloride:

    Type of Bacterium                                                                              Effectiveness [units/ml]                                                    (A)       (B)                                                  ______________________________________                                        Escherichia coli 14                                                                            100         3.12                                             Escherichia coli C 165                                                                         200         6.25                                             Escherichia coli 183/58                                                                        400         6.25                                             Proteus 3400     >400        25                                               Proteus 1017     >400        12.5                                             Pseudomonas aerug. Bonn.                                                                       >400        12.5                                             Pseudomonas aerug. Walter                                                                      >400        25                                               Staphylococcus aur. 133                                                                        12.5        <0.78                                            ______________________________________                                    

EXAMPLE 29 SodiumD(-)-α-(3-cyclohexyloxycarbonyl-3-methyl-ureido)-benzylpenicillin:

4.5 parts by weight of 6-aminopenicillanic acid were suspended in 60parts by volume of 50% strength aqueous tetrahydrofurane, the amount oftriethylamine just sufficient to dissolve the aminopenicillanic acid wasadded, the resulting solution, which had a pH of 8.0 (glass electrode)was cooled to 0°C, and a solution of 8.0 parts by weight ofO-[D(-)-α-(3-cyclohexyloxycarbonyl-3-methylureido)-phenylacetyl]-C-cyano-C-ethoxy-carbonyl-formaldehydeoximein 25 parts by volume of tetrahydrofurane was added dropwise, whilekeeping the pH of the solution at 7.5 by appropriate addition oftriethylamine. Thereafter the mixture was stirred for 90 minutes at22°C, 100 parts by volume of water were added, the solution was adjustedto pH 6.5, the tetrahydrofurane was largely removed in vacuo in a rotaryevaporator, and the remaining aqueous solution was covered with a 1 : 1mixture of ether and ethyl acetate, stirred, cooled to 0° - 5°C andacidified to pH 1.5 with 2 N hydrochloric acid.

The organic phase was then separated off, washed with water and driedover sodium sulphate in a refrigerator, and the sodium salt of thepenicillin was precipitated by means of a 1 M solution of sodium2-ethylhexanoate in ether containing methanol. The supernatant solutionwas decanted from the initially oily precipitate, and the latter wasconverted into a colourless powder by trituration with dry ether.

β-Lactam content: 82%. NMR signals at τ = 2.4-3.0 (5 H), 4.3-4.7 (3 H),5.2 (1 H),

5.8 (1 H), 6.8 (3 H) and 7.9-9.0 ppm (16 H).

The biological activity of this penicillin (A) and of the penicillin (B)prepared from ampicillin and N-cyclohexyloxycarbonyl-N-methyl-carbamicacid chloride were identical within the limit of error, as is shown bythe Table below. Minimum inhibitory concentration in units/ml:

                     A        B                                                   ______________________________________                                        E. coli 14         3.12       1.56                                            E. coli A 261      400        400                                             E. coli C 165      6.25       6.25                                            E. coli 183/58     3.12       1.56                                            Proteus 3400       12.5       6.25                                            Proteus 1017       12.5       6.25                                            Pseudomonas aerug. Bonn                                                                          25         25                                              Pseudomonas aerug. Walter                                                                        50         50                                              Klebsiella K 10    200        100                                             Klebsiella 63      100        100                                             Staphylococcus aureus 1777 E                                                                     200        400                                             Staphylococcus aureus 133                                                                        <0.7       <0.7                                            Enterococcus ATCC 9790                                                                           100        100                                             ______________________________________                                    

EXAMPLE 30 Sodium D(-)-α-(3-allyloxycarbonyl-3-methy-ureido)-benzylpenicillin:

7.1 parts by weight of 6-aminopenicillanic acid were dissolved in amixture of 120 parts by volume of methylene chloride and 10 parts byvolume of triethylamine, 12.4 parts by weight ofO-[D(-)-α-(3-allyloxycarbonyl-3-methylureido)-phenylacetyl]-C-cyano-C-ethoxycarbonyl-formaldehydeoximewere added, the solution was left to stand for 24 hours in arefrigerator, diluted with 150 parts by volume of methylene chloride andexhaustively extracted by shaking with sodium bicarbonate solution, thecombined bicarbonate extracts were covered with a 1 : 1 mixture of etherand ethyl acetate, the pH of the aqueous phase was adjusted to 5.0 with2 N hydrochloric acid, while stirring the organic phase was separatedoff, the aqueous phase was covered with fresh ether-ethyl acetatemixture, the aqueous phase was then acidified to pH 1.5 with 2 Nhydrochloric acid, while stirring and cooling with ice, the organicphase was separated off, and the sodium salt of the penicillin wasprecipitated and isolated in the manner described in Example 29.

Yield: 30%. β-Lactam content: 74%.

    ______________________________________                                        Calculated:                                                                            C 49.7    H 5.2     N 10.5   S 6.1                                   Found:   C 49.9    H 6.1     N 10.4   S 5.6                                   ______________________________________                                    

NMR signals at τ = 2.4-2.8 (5 H), 3.7-4.3 (1 H), 4.4-4.9 (5 H), 5.1-5.4(2 H), 5.8 (1 H), 6.8 (3 H) and 8.45 ppm (6 H).

The biological effectiveness of this penicillin (A) and of thepenicillin (B) prepared from ampicillin andN-allyloxycarbonyl-N-methyl-carbamic acid chloride were identical withinthe limit of error, as is shown by the Table below. Minimum inhibitoryconcentration in units/ml:

                   A          B                                                   ______________________________________                                        E. coli 14       0.8      -    4    3.12                                      E. coli A 261    100      -    500  >400                                      E. coli C 165    4        -    20   12.5                                      E. coli 183/58   4        -    20   6.25                                      Proteus 3400     20       -    100  25                                        Proteus 1017     20       -    100  12.5                                      Pseudomonas aerug. Bonn                                                                        4        -    20   12.5                                      Pseudomonas aerug. Walter                                                                      20       -    100  12.5                                      Klebsiella K 10  20       -    100  50                                        Klebsiella 63    20       -    100  25                                        Staphylococcus aureus 133                                                                      0.8      -    4    0.78                                      Enterococcus ATCC 9790                                                                         20       -    100  50                                        ______________________________________                                    

EXAMPLE 31 Sodiumα-(3-benzeyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin:

This penicillin was prepared in the manner described in Example 30 from2.82 parts by weight of 6-aminopenicillanic acid, 6.0 parts by weight of0[α-(3-benzoyl-3-methylureido)-2,6-dichlorophenylacetyl]-C-cyano-C-ethoxycarbonyl-formaldehydeoxime,50 parts by volume of methylene chloride and 4 parts by volume oftriethylamine.

Yield: 40%. β-Lactam content: 80%.

    ______________________________________                                        Calculated:                                                                            C 47.4    H 4.3     N 8.8   S 5.0                                    Found:   C 47.1    H 4.7     N 8.9   S 5.4                                    ______________________________________                                    

NMR signals at τ = 2.4-2.9 (8 H), 3.3 (0.6 H), 3.8 (0.4 H), 4.45 (2 H),5.8 (1 H), 6.8 (0.6 H). 6.85 (0.4 H) and 8.45 ppm (6 H).

EXAMPLE 32 Sodiumα-(3-benzoyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin:

5.6 parts by weight ofα-(3-benzoyl-3-methylureido)-2,6-dichlorophenylacetic acid weredissolved in a mixture of 70 parts by volume of dry acetone and 2.5parts by volume of triethylamine at -5°C to -10°C, 2.9 parts by weightof 1-methyl-2-chloro-pyrrolinium chloride were added, the mixture wasstirred for 45 minutes, the precipitate thereby formed (triethylaminehydrochloride) was filtered off, the filtrate was combined with asolution of 4.3 parts by weight of 6-aminopenicillanic acid in waterwhich was prepared with the aid of triethylamine, had a pH of 7.5 andwas cooled to -10°C, the mixture was subsequently stirred for 2 hours at-5°C, and the pH was at the same time kept at 7.5 by appropriateaddition of triethylamine. The mixture was then diluted with 130 partsby volume of water, the pH was adjusted to 6.5 by means of 2 Nhydrochloric acid, the acetone was stripped off in vacuo, the solutionwhich remained was adjusted to pH 7.5 and extracted by shaking with a 1: 1 mixture of ether and ethyl acetate, the aqueous phase was separatedoff covered with fresh organic phase, and acidified to pH 1.5 with 2 Nhydrochloric acid, while stirring and cooling in ice, the organic phasewas separated off, washed with water and dried for 2 hours in arefrigerator over sodium sulphate, and the sodium salt of the penicillinwas precipitated and isolated in the manner described in Example 27.

Yield: 33%. β-Lactam content: 78%. NMR signals at τ = 2.4-2.75 (8 H),3.3 (0.7 H), 3.7 (0.3 H), 4.4 (2 H), 5.75 (1 H), 6.8 (3 H) and 8.45 ppm(6 H).

Effectiveness in animal experiments : A and B

EXAMPLE 33 Sodiumα-(3-benzoyl-3-methyl-ureido)-4-methylthiobenzylpenicillin:

This penicillin was prepared, as described in Example 32, from 6.0 partsby weight of α-(3-benzoyl-3-methylureido)-4-methylthiophenylacetic acid,dissolved in 70 parts by volume of acetone and 2.35 parts by volume oftriethylamine, after reaction with 2.7 parts by weight of1-methyl-2-chloropyrrolinium chloride, by combination with a solution of6-aminopenicillanic acid in water, of pH 7.5, prepared by addition oftriethylamine.

Yield: 45% β-Lactam content: 72%. NMR signals at τ = 2.4-2.9 (9 H), 4.4(1 H), 4.5 (2 H), 5.8 (1 H), 6.9 (3 H), 7.6 (3 H) and 8.45 ppm (6 H).

Effectiveness in animal experiments : A and B

EXAMPLE 34 Sodiumα-(3-ethoxycarbonyl-3-methyl-ureido)-4-methylthiobenzylpenicillin:

This penicillin was prepared in the manner described in Example 32 from6.0 parts by weight ofα-(3-ethoxycarbonyl-3-methylureido)-4-methylthiophenylacetic acid, 80parts by volume of acetone, 2.6 parts by volume of triethylamine and 3.0parts by weight of 1-methyl-2-chloropyrrolinium chloride, by combinationwith a solution of 4.4 parts by weight of 6-aminopenicillanic acid in 70parts by volume of 50% strength aqueous acetone, prepared by addition oftriethylamine.

Yield: 44%. β-Lactam content; 78%. NMR signals at τ = 2.6 (2 H), 2.75 (2H), 4.5 (1 H), 4.55 (2 H), 5.5-5.9 (3 H), 6.85 (3 H), 7.55 (3 H), 8.4 (6H) and 8.6 ppm (3 H).

EXAMPLE 35 Sodiumα-(3-ethoxycarbonyl-3-methyl-ureido)-4-methylthiobenzylpenicillin:

To prepare this penicillin, 6.0 parts by weight ofα-(3-ethoxycarbonyl-3-methylureido)-4-methylthiophenylacetic acid weredissolved in 80 parts by volume of acetone, with the addition of 2.6parts by volume of triethylamine, 3.0 parts by weight of1-methyl-2-chloro-pyrrolinium chloride were added at -5°C to -10°C, themixture was stirred for 45 minutes at the same temperature, a solutionof 4.4 parts by weight of 6-aminopenicillanic acid in a mixture of 70parts by volume of 50% strength aqueous acetone and triethylamine, whichhad a pH of 7.5, was added, the mixture was subsequently stirred for 2hours at -5°C and diluted with 150 parts by volume of water, and thereaction mixture was worked up as in Example 32, to isolate the sodiumsalt of the penicillin.

Yield: 44%. β-Lactam content: 78%.

    ______________________________________                                        Calculated:                                                                            C 46.7    H 5.2     N 9.9   S 11.3                                   Found:   C 47.0    H 5.6     N 9.4   S 10.8                                   ______________________________________                                    

NMR signals as indicated in Example 34. The spectra of both substancesare identical.

Effectiveness in animal experiments: A

EXAMPLE 36 Sodiumα-(3-β-chloropropionyl-3-methyl-uredo)-cyclohex-3-enylmethylpenicillin:

This penicillin was prepared in the manner described in Example 32, from5.3 parts by weight ofα-(3β-chloropropionyl-3-methylureido)-cyclohex-3-enyl-acetic acid, afterreaction with 3.0 parts by weight of 1-methyl-2-chloro-pyrroliniumchloride in the presence of 2.6 parts by volume of triethylamine, byreaction with 4.4 parts by weight of 6-aminopenicillanic acid which hadbeen dissolved in 50% strength aqueous acetone, at pH 7.5, by means oftriethylamine,

Yield: 44%, β-Lactam content: 78%, NMR signals at τ = 4.3 (2 H), 4.5 (2H), 5.8 (1 H), 6.2 (2 H), 6.65 (3 H), 6.8 (2 H) and 7.7 - 8.8 ppm (13H).

EXAMPLE 37 SodiumD(-)-α-[3-(2-thenoyl)-3-methyl-ureido]-benzylpenicillin:

To prepare this penicillin, 3.9 parts by weight ofD(-)-α-[3-(2-thenoyl)-3-methyl-ureido]-phenylacetic acid were dissolvedin 55 parts by volume of acetone with the addition of 2.0 parts byvolume of triethylamine, 2.3 parts by weight of1-methyl-2-chloropyrrolinium chloride were added at -5°C to -10°C, themixture was stirred for 45 minutes at the same temperature, a solutionof 3.1 parts by weight of 6-aminopenicillanic acid in a mixture of 60parts by volume of 90% strength aqueous acetone and triethylamine, whichhad a pH of 7.5, was added, and the mixture was stirred for 2 hours at-5°C and worked up - as described in Example 32 - to isolate the sodiumsalt of the penicillin. Yield: 56%. β-Lactam content: 64%. NMR signalsat τ = 2.1-3.0 (8 H), 4.35-4.8 (3 H), 5.8 (1 H), 6.55 (3 H) and 8.45 ppm(6 H).

EXAMPLE 38 SodiumD(-)-α-[3-(3,5-dimethylisoxazoloyl-4)-3-methyl-ureido]-benzylpenicillin:

To prepare this penicillin, 3.9 parts by weight ofD-α-[3-(3,5-dimethylisoxazoloyl-4)-3-methyl-ureido]-phenylacetic acidwere dissolved in 60 parts by volume of methylene chloride with theaddition of 2.0 parts by volume of triethylamine, the solution wascooled to -10°C, 2.2 parts by weight of 1-methyl-2-chloropyrroliniumchloride were added, and the mixture was left to stand for 90 minutes at-10° to -35°C (solution A).

Separately, 3.1 parts by weight of 6-aminopenicillanic acid weresuspended in 60 parts by volume of methylene chloride, 3.4 parts byvolume of triethylamine were added, and the mixture was stirred for 4hours at 22°C (solution B). Solution B was then cooled to between 0 and-5°C, and solution A was added in several portions, over the course of30 minutes, while stirring and continuing to cool.

Thereafter the mixture was stirred for a further hour at 0° to 5°C, thesolvent was stripped off in vacuo, the residue was taken up in water anda 1 : 1 mixture of ether and ethyl acetate, the pH was adjusted to 7.5while stirring, the organic phase was separated off, the aqueous phasewas covered with fresh ether-ethyl acetate mixture, the pH was broughtto 1.5 by means of 2 N hydrochloric acid, while stirring and coolingwith ice, the organic phase was separated off, washed with water anddried over magnesium sulphate for 2 hours in a refrigerator, and thepenicillin was isolated as the sodium salt, as described in Example 32.Yield: 50% β-Lactam content: 80%.

    ______________________________________                                        Calculated:                                                                            C 50.7    H 5.0     N 12.3  S 5.6                                    Found:   C 51.1    H 5.4     N 11.6  S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.35-2.9 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.8(3 H), 7.6 (3 H), 7.75 (3 H) and 8.45 ppm (6 H).

EXAMPLE 39

If, in the procedure of Example 37, theD(-)-α-[3-(2-thenoyl)-3-methylureido]-phenylacetic acid used there isreplaced by 0.012 mol of:

D(-)-α-[3-(2-furoyl)-3-methyl-ureido ]-phenylacetic acid,

D(-)-α-[3-(2-furoyl)-3-ethyl-ureido ]-phenyl-acetic acid,

D(-)-α-[3-(2-furoyl)-3-n-propyl-ureido]-phenylacetic acid,

D(-)-α-[3-(2-furoyl-3-phenyl-ureido]-phenylacetic acid,

D(-)-α-[3-(2,5-dimethylfuroyl-3-)-3-methyl-ureido]-phenylacetic acid,

D(-)-α-[3-(5-bromofuroyl-3-)-3-methyl-ureido ]-phenylacetic acid,

D-(-)-α-[3-(5-methoxymethylfuroyl-2-)3-methyl-ureido]-phenylacetic acid,

D(-)-α-[3-(3,5-dimethylisothiazol-3-yl)-carbonyl)-3-methyl-ureido]-phenylaceticacid,

D(-)-α-[3-(isoxazol-4-yl)-carbonyl-3-methyl-ureido]-phenylacetic acid,

D(-)-α-[3-(isoxazol-3-yl)-carbonyl-3-methyl-ureido]-phenylacetic acid,

D(-)-α-[3-(3-methylthiodiazol(1,2,5)-4-yl)-carbonyl-3-methyl-ureido]-phenylaceticacid or

D(-)-α-[3-(4-methylthiadiazol(1,2,3)-5-yl)-carbonyl-3-methyl-ureido]-phenylaceticacid

the sodium salts of the following penicillins are obtained:

D(-)-α-[3-(2-furoyl)-3-methyl-ureido]-benzylpenicillin,

D(-)-α-[3-(2-furoyl)-3-ethyl-ureido]-benzylpenicillin,

D(-)-α-[3-(2-furoyl)-3-n-propyl-ureido]-benzylpenicillin,

D(-)-α-[3-(2-furoyl)-3-phenyl-ureido]-benzylpenicillin,

D(-)-α-[3-(2,5-dimethylfuroyl-3)-3-methyl-ureido]-benzylpenicillin,

D(-)-α-[3-(5-bromofuroyl-3)-3-methyl-ureido]-benzylpenicillin,

D(-)-α-[3-(5-methoxymethylfuroyl-2)-3-methyl-ureido)-benzylpenicillin

D(-)-α-[3-(3,5-dimethylisothiazol-3-yl)-carbonyl-3-methyl-ureido]-benzylpenicillin,

D(-)-α-[3-(isoxazol-4-yl)-carbonyl-3-methyl-ureido]-benzylpenicillin,

D(-)-α-[3-isoxazol-3-yl)-carbonyl-3-methyl-ureido]-benzylpenicillin,

D(-)-α-[3-(3-methylthiodiazol(1,2,5)-4-yl)-carbonyl-3-methyl-ureido]-benzylpenicillinor

D(-)-α-[3-(4-methylthiodiazol(1,2,3)-5-yl)-carbonyl-3-methyl-ureido]-benzylpenicillin.

EXAMPLE 40 A)d(-)-α-(3-Cyclohexyloxycarbonyl-3-methyl-ureido)-phenyl-acetic acid:

13.5 parts by weight of bis-(trimethylsilyl)-C-phenylglycine weredissolved in 100 parts by volume of dry carbon tetrachloride, a solutionof 10.0 parts by weight of N-cyclohexyloxycarbonyl-N-methyl-carbamicacid chloride in 30 parts by volume of carbon tetrachloride was slowlyadded dropwise at 0°C while excluding moisture, and the mixture was leftto stand overnight in a refrigerator. Thereafter it was washed 3 timeswith 50 parts by volume of water at a time, and the organic phase wasevaporated to dryness in vacuo.

Yield of oily product: 95%. NMR signals at τ = 0.5 (1 H), 2.5 (5 H), 4.6(1 H), 5.2 (1 H), 6.8 (3 H) and 7.9-8.9 ppm (10 H).

(B)0-[D(-)-α-(3-Cyclohexyloxycarbonyl-3-methyl-ureido)-phenylacetyl]-C-cyano-C-ethoxycarbonyl-formaldehydeoxime:

2.92 parts by weight of C-cyano-C-ethoxycarbonyl-formaldehydeoxime weredissolved in 50 parts by volume of tetrahydrofurane, 2.9 parts by volumeof triethylamine were added, the mixture was cooled to -10°C, 1.5 partsby volume of thionyl chloride were then slowly added dropwise whilestirring and continuing to cool, and the mixture was subsequentlystirred for 15 minutes at -10°C. A solution, cooled to 0°C, of 6.88parts by weight ofD(-)-α-(3-cyclohexyloxycarbonyl-3-methyl-ureido)-phenylacetic acid in amixture of 50 parts by volume of tetrahydrofurane and 2.9 parts byvolume of triethylamine was then added dropwise over the course ofapprox. 45 minutes while continuing to cool, and the reaction mixturewas subsequently stirred for a further hour at 0°C. The triethylaminehydrochloride which had separated out was then filtered off, thefiltrate was evaporated in vacuo from a bath at 15°- 20°C, using arotary evaporator, the residue was dissolved in methylene chloride, thesolution was cooled to 0°C and once shaken rapidly with ice water, andthe organic phase was subsequently dried at 0°C over sodium sulphate,filtered, and evaporated in vacuo by means of a rotary evaporator, froma bath at 20°C, and finally from a bath at 40°C. A colourless,varnish-like substance is obtained.

Yield: 98%. Specific rotation: [α]₅₈₉ -8.1° (54.2 mg; methanol).

The substance showed an IR spectrum corresponding to its structure.

NMR signals at τ = 0.5 (1 H), 2.6 (5 H), 4.3 (1 H), 5.25 (1 H), 5.7 (2H), 6.8 (3 H) and 8.0-9.0 ppm (13 H).

EXAMPLE 410-[D(-)-α-(3-Allyloxycarbonyl-3-methyl-ureido)-phenylacetyl]-C-cyano-C-ethoxycarbonyl-formaldehydeoxime:

This substance was prepared in the manner described in Example 40, from5.86 parts by weight of C-cyano-C-ethoxycarbonyl-formaldehydeoxime, 100parts by volume of tetrahydrofurane, 57 parts by volume oftriethylamine, 3.0 parts by volume of thionyl chloride and a mixture of12.0 parts by weight ofD(-)-α-(3-allyloxycarbonyl-3-methyl-ureido)-phenylacetic acid, 100 partsby volume of tetrahydrofurane and 5.7 parts by volume of triethylamine.A colorless, varnish-like substance is obtained.

Yield: over 80%. Specific rotation: [α]₅₈₉ -19.6° (50.6 mg; methanol).

The substance showed an IR spectrum corresponding to its structure.

NMR signals at τ = 0.4 (1 H), 2.6 (5 H), 3.7-4.2 (1 H), 4.3 (1 H),4.5-4.9 (2 H), 5.3 (2 H), 5.65 (2 H), 6.8 (3 H) and 8.65 ppm (3 H).

EXAMPLE 420-[D(-)-α-(3-benzoyl-3-methyl-ureido)-2,6-dichlorophenylacetyl]C-cyano-C-ethoxycarbonyl-formaldehydeoxime:

This substance was prepared in the manner described in Example 40, from2.85 parts by weight of C-cyano-C-ethoxycarbonyl-formaldehydeoxime, 50parts by volume of tetrahydrofurane, 2.8 parts by volume oftriethylamine, 1.45 parts by volume of thionyl chloride and a mixture of7.6 parts by weight ofD(-)-α-(3-benzoyl-3-methyl-ureido)-2,6-dichlorophenylacetic acid, 50parts by volume of tetrahydrofurane and 2.8 parts by volume oftriethylamine. A colorless, varnish-like substance was obtained.

Yield: over 80%.

The IR spectrum of the substance showed the bands corresponding to itsstructure.

NMR signals at τ = 0.5 (1 H), 2.45 (5 H), 3.55 (1 H), 5.65 (2 H), 6.9 (3H) and 8.7 (3 H).

EXAMPLE 43 Sodiumα-(pyrrolid-2-on-1-yl-carbonylamino)-α-p-tolyl-methylpenicillin:

This penicillin was prepared in the manner described in Example 1, from14.5 parts by weight ofα-pyrrolid-2-on-1-yl-carbonylamino)-α-p-tolylacetic acid, 10.2 parts byweight of tetramethyl-chloroformamidinium chloride and 15 parts byweight of 6-amino-penicillanic acid.

Yield: 29% β-Lactam content: 67% NMR signals at τ = 2.5 - 3.05 (4 H),4.5 (3 H), 5.8 (1 H), 6.1 - 6.4 (2 H), 7.4 (2 H), 7.7 (3 H), 8.0 (2 H)and 8.3 - 8.6 ppm (6 H).

EXAMPLE 44 Sodiumα-(3-o-fluorobenzoyl-3-methyl-ureido)-α-p-tolyl-methylpenicillin:

This penicillin was prepared in the manner indicated in Example 2, from9 parts by weight of N-o-fluorobenzoyl-N-methylureido-N-p-tolylaceticacid, 4.95 parts by weight of tetramethyl-chloroformamidinium chlorideand 8.5 parts by weight of 6-amino-penicillanic acid.

Yield: 59% β-Lactam content: 87%

    ______________________________________                                        Calculated:                                                                            C 53.7    H 4.8     N 9.7   S 5.5                                    Found    C 53.4    H(6.0)    N 9.7   S 5.9                                    ______________________________________                                    

NMR signals at τ = 2.3 - 3.1 (8 H), 4.5 (3 H), 5.8 (1 H), 6.3 (3 H), 7.7(3 H) and 8.2 - 8.5 ppm (6 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 45 Sodiumα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin:

3.76 parts by weight of tetramethylchloroformamidinium chloride weresuspended in 15 parts by volume of dry acetone and stirred for 10minutes with exclusion of moisture. The product was filtered off, againwith exclusion of moisture, and the reagent was suspended in 40 parts byvolume of methylene chloride and cooled to 0°C. 5.53 parts by weight ofα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methylphenylacetic acid ina little methylene chloride were now added and a solution of 2.0 partsby weight of triethylamine in 20 parts by volume of methylene chloridewas added dropwise to the mixture over the course of 30 minutes, whilestirring and excluding moisture. The mixture was stirred for a further20 minutes at +5°C and then cooled to -20°C and treated, all at once,with a solution of the triethylamine salt of 6-aminopenicillanic acid inmethylene chloride, also cooled to -20°C. (This solution had beenprepared by stirring 5.8 parts by weight of 6-aminopenicillanic acid,3.4 parts by weight of triethylamine and 8 parts by weight of anhydroussodium sulphate in 40 parts by volume of methylene chloride for 2 hours,and subsequent filtering). The mixture was left to reach 0°C whilestirring, was treated with a further 0.9 part by weight of triethylamineafter a short time, and was further stirred for 30 minutes at 0°C and 30minutes at room temperature. It was now poured into ice water, the pHvalue was adjusted to 5.5 and the methylene chloride was stripped off invacuo. The residue was twice extracted with ether and the ether waseluted with a little water. The combined aqueous solutions were coveredwith a layer of ethyl acetate and adjusted to a pH value of 1.5 withdilute hydrochloric acid while stirring and cooling with ice. The ethylacetate phase was separated off, the water was again extracted withethyl acetate, and the combined extracts were washed with water. Theywere dried for about 1 hour at 0°C over MgSO₄, filtered and treated with20 parts by volume of a 1 molar solution of sodium 2-ethylhexanoate inether containing methanol, and the mixture was evaporated in vacuo atroom temperature until it acquired an oily consistency. It was nowdissolved in the requisite amount of methanol and this solution wasadded dropwise to 500 parts by volume of a mixture of about 500 parts byvolume of absolute ether and 50 parts by volume of methanol, whilestirring vigorously. The product which precipitated was filtered offafter standing for a short time, suspended in dry ether and againfiltered off. It was dried in vacuo over P₂ O₅ for about 2 days.

Yield: 70% β-Lactam content: 86% NMR signals, see Table 2, page 96, IRbands at 3280, 1760, 1712, 1655, 1600, 1520, 1270 and 765 cm⁻ ¹ (inNujol suspension).

EXAMPLE 46 Sodiumα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin:

2.8 parts by weight ofα-[(imidazolidin-2-on-1-yl)carbonylamino]-p-methylphenylacetic acid werereacted, in the manner described in Exampale 45, with 1.7 parts byweight of 1-methyl-2-chloro-Δ 1-pyrrolinium chloride instead oftetramethyl-chloroformamidinium chloride, and subsequently with 2.6parts by weight of 6-aminopenicillanic acid in the form of itstriethylamine salt, to give the sodium salt ofα-[(imidazolidin-2-on-1-yl)-carbonylamino]

Yield: 54% β-Lactam content: 39% NMR signals, see Table 2.

The position of the IR bands agrees with that of the penicillin ofExample 45.

EXAMPLE 47 Sodium α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin:

This penicillin was manufactured in the manner described in Example 1,from 5.95 parts by weight ofα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorophenylacetic acid,3.76 parts by weight of tetramethylchloroformamidinium chloride and 5.8parts by weight of 6-aminopenicillanic acid.

Yield: 59% β-Lactam content: 86% NMR signals, see Table 2. IR bands at3300, 1775, 1727, 1667, 1608, 1540, 1287 and 780 cm⁻ ¹.

EXAMPLE 48 A Sodiumα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin:

3.6 parts by weight ofα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorophenylacetic acidwere reacted in the manner described in Example 1 with 2.22 parts byweight of 1,3-dimethyl-2-chloro-Δ-1-imidazolinium chloride andsubsequently with 3.02 parts by weight of 6-aminopenicillanic acid togive the sodium salt ofα-[(imidazolidin-2-on-1-yl)carbonylamino]-p-chlorobenzylpenicillin.

Yield: 65% β-Lactam content: 72% NMR signals, see Table 2.

The IR spectrum in Nujol is identical with that of the penicillin ofExample 47.

EXAMPLE 48 Bα-[(Imidazolidin-2-on-1-yl)-carbonylamino]-p-methylphenylacetic acid:

16.5 parts by weight of α-(4-methylphenyl)-glycine were dissolved in 200parts by volume of 50% strength aqueous dioxane, with the addition ofsufficient 2 N sodium hydroxide solution. Thereafter the mixture wasadjusted back to a pH value of 7-8 with 5 N hydrochloric acid, whereuponthe aminoacid separated out partially as a fine precipitate. A solutionof 11.8 parts by weight of 1-chlorocarbonyl-imidazolidin-2-one in 50parts by volume of warm acetone was now added dropwise, while stirringand cooling by means of an ice bath. The pH was at the same timemaintained at between 7 and 8 by appropriate addition of 2 N sodiumhydroxide solution. After completion of the addition, the mixture wasstirred for a further 15 minutes at room temperature until the pH valueremained constant. Unreacted aminoacid (6 parts by weight) was filteredoff, and the filtrate was evaporated to half its volume in vacuo andextracted once with 100 parts by volume of ether. The aqueous phase wasadjusted to a pH of 1-2 with 2 N hydrochloric acid and the oil whichprecipitated was taken up in ethyl acetate by extraction with 2 × 100parts by volume. The combined ethyl acetate extracts were washed with 50parts by volume of water, dried over MgSO₄ and subsequently evaporatedto dryness. A glassy foam was obtained, which through trituration withpetroleum ether was converted into a finely granular, non-crystallinepowder.

Yield: 48%. NMR signals, see Table 2.

EXAMPLE 48 C

The following α-[(imidazolidin-2-on-1-yl)-carbonylamino]phenylaceticacid was produced as described in Example 48 B:α-[(Imidazolidin-2-on-1-yl)carbonylamino]-p-chlorophenylacetic acid from18.6 parts by weight of α-(4-chlorophenyl)-glycine and 11.8 parts byweight of 1-chlorocarbonylimidazolidin-2-one. Recovered unreactedα-(4-chlorophenyl)glycine: 6 parts by weight.

Yield of product moist with ether: 33 parts by weight.

The substance was recrystallised from ethyl acetate/petroleum ether.

    ______________________________________                                        1st fraction, yield:                                                                       35%     relative to converted starting                           2nd fraction, yield:                                                                       15%     material.                                                ______________________________________                                    

Melting point = 115°-120°C. NMR signals, see Table 2.

EXAMPLE 48 D 1Chlorocarbonyl-imidazolidin-2-one:

4 parts by weight of phosgene in 10 parts by volume of absolutetetrahydrofurane were added dropwise, over the course of 15 minutes, toa vigorously stirred solution of 3.5 parts by weight ofimidazolidone-(2) [manufactured according to Fischer and Koch, Ann. 232,page 224 (1886)] in 50 parts by volume of absolute tetrahydrofurane.Thereafter the reaction mixture was stirred for 3 hours at 10°C and astream of dry air was then passed through it to blow out thehydrochloric acid produced, and residues of phosgene. It was nowevaporated to dryness in vacuo on a rotary evaporator, and the solidresidue was dried over concentrated sulphuric acid at about 12 mm Hg.

Yield: 93%. Melting point = 150°C after recrystallisation fromacetone-pentane.

    ______________________________________                                        Calculated:                                                                            C 32.3    H 3.4     N 18.8  Cl 23.9                                  Found:   C 32.3    H(4.5)    N 18.7  Cl 23.9                                  ______________________________________                                    

NMR signals at τ = 5.7 to 6.1 (2 H) and 6.3 to 6.7 (2 H), (acetone-d₆ asthe solvent), symmetrical A₂ B₂ -system. IR bands at 3230, 1790, 1700,1270 and 1150 cm⁻ ¹.

EXAMPLE 48 E

If, in the procedure of Example 45, theα-[(imidazolidin2-on-1-yl)-carbonylamino]-p-methylphenylacetic acid usedtherein is replaced by 0.02 mol of one of the following:

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-thienyl(2)-acetic acid,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-thienyl(3)-acetic acid,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxyphenylacetic acid,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-m-hydroxyphenylacetic acid,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o-chlorophenylacetic acid,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-di-fluorophenylaceticacid,

α-[(imidazolidin-2-on-1-yl)-carbonyl-amino]-o,o'-chlorofluorophenylaceticacid or

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-acetylaminophenylaceticacid,

the following penicillins are obtained in the form of their sodiumsalts:

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-thienyl 2)-methylpenicillin,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-thienyl(3)-methylpenicillin,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-m-hydroxybenzylpenicillin,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o-chlorobenzylpenicillin,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]o,o'-difluorobenzylpenicillin,

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-chlorofluorobenzylpenicillinor

α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-acetylaminobenzylpenicillin.

EXAMPLE 49 D(-)-α-[(Imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid:

9.7 parts by weight of D(-)-C-phenylglycine were suspended in 150 partsby volume of 50% strength aqueous dioxane and sufficient 40% strengthaqueous sodium hydroxide solution was added dropwise at roomtemperature, while stirring, for the phenylglycine to have justdissolved. Approximately 15% strength hydrochloric acid was then addedto this solution, while stirring, until the pH of the solution hadreached 7.5 - 8.0. The fine suspension of the phenylglycine which ispresent at that stage was cooled to about +5°C, 10.6 parts by weight offinely powdered imidazolidin-2-on-1-yl-carbonyl chloride were graduallyintroduced at this temperature, while stirring, and at the same time thepH was kept at 7.5 - 8.0 by appropriate addition of approximately 5 Nsodium hydroxide solution. The phenylglycine hereupon dissolved, apartfrom a small amount of residue. The mixture was stirred for a further 60minutes at +5°C, during which time a little sodium hydroxide solutionstill had to be added occasionally in the first 15 minutes only, tomaintain the desired pH. Small amounts of insoluble matter were thenfiltered off. The filtrate was largely freed of dioxane by means of arotary evaporator, covered with a layer of ethyl acetate, acidified with2 N hydrochloric acid to pH 1.5 - 2.0 and thoroughly stirred, and theorganic phase was then separated off, twice washed with water, driedover magnesium sulphate and completely evaporated in a rotaryevaporator. The residue, a colorless clear foam, was dried for 2 daysover P₄ O₁₀ in a desiccator with an open tap, connected to an oil pump.Yield: 7.9 parts by weight. In the IR spectrum (solvent:dimethylsulphoxide), the substance shows two double bands in the regionleft open by the solvent, namely at 1720 and 1670, and at 1525 and 1480cm⁻ ¹ , respectively. NMR signals, see Table 2.

EXAMPLE 50α-[(Imidazolidin-2-on-1-yl)-carbonylamino]-4-methylthiophenylaceticacid:

(a) α-Amino-4-methylthiophenylacetic acid:

This aminoacid was obtained according to the usual procedure: startingfrom 4-methylthiobenzaldehyde, via the cyanohydrin and α-aminonitrile,and its saponification with boiling 20% strength hydrochloric acid.Melting point >260° on the Kofler bench.

The IR spectrum (Nujol) shows a single band in the carbonyl region at1740 cm⁻ ¹ and a broad absorption between 1570 and 1670 cm⁻ ¹, with amain peak at 1590 cm⁻ ¹.

The NMR spectrum (NaOD/D₂ O) shows signals at τ = 2.5-2.8 (4 H)(AB-system), at 5.6 (1 H) and at 7.6 ppm (3 H).

α-[(Imidasolidin-2-on-1-yl)-carbonylamino]-4-methylthiophenylaceticacid:

This compound was manufactured from 13 parts by weight of the aminoaciddescribed above and 10 parts by weight ofimidazolidin-2-on-1-yl-carbonyl chloride, in the manner described inExample 5.

Yield: 6.7 parts by weight of a yellowish hard foam. In the IR spectrum(solvent: dimethylsulphoxide) the substance shows two double bands inthe range left open by the solvent, namely at 1710 and 1660, and at 1520and 1480 cm⁻ ¹. NMR signals, see Table 2.

EXAMPLE 51 SodiumD(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:

3.8 parts by weight ofD(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-phenylacetic acid weredissolved in 65 parts by volume of dichloromethane, 2.7 parts by weightof 1-methyl-2-chloro-Δ1-pyrrolinium chloride were added, and aftercooling to -10°C 2.0 parts by volume of triethylamine were addedgradually. This reaction mixture was then stirred for one hour at -5°C(mixture A). 4.0 parts by weight of 6-aminopenicillanic acid in 80 partsby volume of dichloromethane were treated with 4.4 parts by volume oftriethylamine and 4.0 parts by weight of anhydrous sodium sulphate andthen stirred for two hours at room temperature. After filtration, thesolution was cooled to -20°C and combined with the mixture A. Thereaction mixture was left to reach 0°C of its own accord, and was thenstirred for a further hour at 0°C. The solvent was now removed in arotary evaporator, the residue was dissolved in water, and the solutionwas covered with a layer of ethyl acetate and acidified with dilutehydrochloric acid at 0° to 5°C, while stirring, until pH 1.5 wasreached. The organic phase was then separated off, washed with water,dried over magnesium sulphate while cooling, and filtered, and afterdilution with an equal amount of ether the sodium salt of the penicillinwas precipitated from the filtrate by adding a solution of sodium2-ethylcaproate dissolved in ether containing methanol.

Yield: 1.3 parts by weight. β-Lactam content: 34%. IR band at 1775 cm⁻¹. NMR signals, see Table 2.

EXAMPLE 52D(-)-α-[(Imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin (freeacid and sodium salt):

Mixture A was prepared in a corresponding manner to Example 51, from 3.8parts by weight ofD(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-phenylacetic acid, 65parts by volume of dichloromethane, 3.0 parts by weight of1,3-dimethyl-2-chloro-Δ-1-imidazolinium chloride and 2.0 parts by volumeof triethylamine, and reacted with the dried solution prepared from 4.0parts by weight of 6-aminopenicillanic acid, 80 parts by volume ofdichloromethane, 4.4 parts by volume of triethylamine and 4.0 parts byweight of Na₂ SO₄. After removing the solvent and distributing thereaction product between an aqueous phase of pH 1.5 and ethyl acetate, aprecipitate which is neither soluble in the acid aqueous phase nor inthe organic phase was formed and this was filtered off, washed withwater and dried. This product was the free acid of the desiredpenicillin. Yield 1.5 parts by weight. The ethyl acetate phase which wasabove the acid aqueous phase was separated off, washed with water, driedover magnesium sulphate and diluted with ether, and the sodium salt ofthe penicillin was precipitated.

Yield: 1.9 parts by weight. β-Lactam content (free acid): 92%. β-Lactamcontent (sodium salt): 89%. The two penicillins show an IR spectrumwhich corresponds to their structure.

NMR signals, see Table 2.

EXAMPLE 53D(-)-α-[(Imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin (freeacid and sodium salt):

The penicillin was prepared in a manner corresponding to Example 52,from 3.8 parts by weight ofD(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-phenylacetic acid, 50parts by volume of dichloromethane, 1.2 parts by weight oftetramethylchloroformamidinium chloride and 1.0 part by volume oftriethylamine, constituting mixture A, and 2.0 parts by weight of6-aminopenicillanic acid in 50 parts by volume of dichloromethane and2.2 parts by volume of triethylamine as well as 2.0 parts by weight ofsodium sulphate. 0.2 part by weight of penicillin was obtained as thefree acid and 1.9 parts by weight as the sodium salt.

β-Lactam content (free acid): 90%. β-Lactam content (sodium salt): 25%.

The free acid showed an IR spectrum corresponding to its structure.

EXAMPLE 54 Sodiumα-[(imidazolidin-2-on-1-yl)-carbonylamino]-4-methylthiobenzylpenicillin:

This penicillin was prepared in a manner corresponding to Example 51,from 4.5 parts by weight ofα-[(imidazolidin-2-on-1-yl)-carbonylamino]-4-methylthio-phenylaceticacid, 80 parts by volume of dichloromethane, 2.7 parts by weight of1-methyl-2-chloro-Δ1-pyrrolinium chloride and 2.0 parts by volume oftriethylamine, constituting mixture A, and 4.0 parts by weight of6-aminopenicillanic acid, 80 parts by volume of dichloromethane, 4.4parts by volume of triethylamine and 4.0 parts by weight of sodiumsulphate.

Yield: 4.2 parts by weight of sodium salt. β-Lactam content: 36%. NMRsignals, see Table 2.

EXAMPLE 55 Sodiumα-[(imidazolidin-2-on-1-yl)-carbonylamino]-4-methylthiobenzylpencillin:

This penicillin was obtained in a manner based on Example 51, from 1.9parts by weight ofα-[(imidazolidin-2-on-1-yl)-carbonylamino]-4-methylthio-phenylaceticacid, 40 parts by volume of dichloromethane, 1.2 parts by weight oftetramethylchloroformamidinium chloride and 0.98 part by volume oftriethylamine constituting mixture A, and 1.73 parts by weight of6-aminopenicillanic acid, 40 parts by volume of dichloromethane, 1.9parts by volume of triethylamine and 1.5 parts by weight of sodiumsulphate constituting mixture B. Yield: 2.0 parts by weight of sodiumsalt. β-Lactam content: 61%. The pencillin showed an IR spectrumcorresponding to its structure.

NMR signals, see Table 2.

EXAMPLE 56 1,3-Dimethyl-2-chloro-Δ1-imidazolinium chloride:

(a) N,N'-Dimethyl-N,N'-bis-trimethylsilyl-ethylenediamine:

A mixture of 176 parts by weight of N,N'-dimethylethylenediamine, 1000parts by volume of benzene and 552 parts by volume of triethylamine werestirred at room temperature and at the same time 434 parts by weight oftrimethylchlorosilane, diluted with 500 parts by volume of benzene, wereadded dropwise over the course of 3 hours. The mixture was stirred for afurther 3.5 hours and left to stand overnight, and the precipitatepresent was filtered off and washed with benzene. The combined filtrateswere concentrated in a rotary evaporator and the residue was distilledin vacuo.

Yield: 364 parts by weight. Boiling point 0.15 = 55°-60°C.

The NMR spectrum (CCl₄ as the solvent) showed signals at -160 (4 H) and-148 Hz (6 H), with the signal of the trimethylsilyl radicals (9 H)being at 0 Hz.

    ______________________________________                                        Analysis:                                                                             Calculated:                                                                              C 51.7    H 12.1  N 12.1                                           Found:     C 51.1    H 11.9  N 12.1                                   ______________________________________                                    

(b) N,N'-Dimethylimidazolidone-(2).

A solution of 363 parts by weight ofN,N'-dimethyl-N,N'-bis-trimethylsilyl-ethylenediamine in 440 parts byvolume of dichloromethane, and a solution of 170 parts by weight ofphosgene in 700 parts by volume of dichloromethane, were simultaneouslyand separately added dropwise, over the course of 4.5 hours, to 800parts by volume of dichloromethane at room temperature, while stirring.The reaction mixture was then left to stand overnight, the unreactedphosgene was flushed out with dry air, the solvent was removed in arotary evaporator and the residue was distilled in vacuo. Yield 119parts by weight. Boiling point 10-10.5 mm Hg = 95°-95.5°C.

(c) 1,3-Dimethyl-2-chloro-Δ-1-imidazolinium chloride:

A solution of 150 parts by weight of 1,3-dimethylimidazolidone-(2) in200 parts by volume of toluene was added to a solution of 156 parts byweight of phosgene in 330 parts by volume of toluene, and the mixturewas left to stand overnight at room temperature. The product which hadthen crystallised out was filtered off, washed with carbon tetrachlorideand dried over P₄ O₁₀ in a desiccator.

Yield 177 parts by weight.

Melting point: about 95°-100°C (Kofler bench). The product iscrystalline and very hygroscopic. The NMR spectrum (solvent:chloroform)shows signals at τ = 5.6 (4 H) and 6.65 ppm (6 H).

EXAMPLE 57

If, in the procedure of Example 45, theα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methylphenylacetic acidused therein is replaced by 0.02 mol of:

D(-)-α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-methylphenylaceticacid,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-chlorophenylaceticacid,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-methylthiophenylaceticacid,

α-[(diazacyclohexan-2-on-1-yl)-carbonylamino]-p-hydroxyphenylaceticacid,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-thienyl(2)-aceticacid,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-thienyl(3)-aceticacid,

D(-)-α-[(benzimidazolon-1-yl)-carbonylamino]-phenylacetic acid,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-methylphenylacetic acid,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-chlorophenylacetic acid,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-methylthio-phenylacetic acid,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-hydroxy-phenylacetic acid,

α-[(benzimidazolon-1-yl)-carbonylamino]-thienyl(2)-acetic acid,

α-[(benzimidazolon-1-yl)-carbonylamino]-thienyl(3)-acetic acid,

D(-)-α-[(5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,α-[(4-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylphenylaceticacid,

α-[(5-methylimidazolidin-2-on-1-yl, -carbonylamino]-p-chlorophenylaceticacid,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiophenylaceticacid,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxyphenylaceticacid,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-thienyl(2)-aceticacid,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-thienyl(3)-aceticacid,

D(-)-α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylphenylaceticacid,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-chlorophenylaceticacid,

α-[(4,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiophenylaceticacid,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxyphenylaceticacid,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-thienyl(2)-acetic acid or

α-[(4,4-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-thienyl(3)-acetic acid,

the following penicillins are obtained in the form of their sodiumsalts:

D(-)-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-methylthio-benzylpenicillin,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-α-thienyl(2)methylpenicillin,

α-[(1,3-diazacyclohexan-2-on-1-yl)-carbonylamino]-α-thienyl(3)methylpenicillin,

D(-)-α-[(benzimidazolon-1-yl)-carbonylamino]-benzylpenicillin,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-methyl-benzylpenicillin,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(benzimidazolon-1-yl)-carbonylamino]-p-methylthio-benzylpenicillin

α-[(benzimidazolon-1-yl)-carbonylamino]-p-hydroxy-benzylpenicillin,

α-[(benzimidazolon-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

α-[(benzimidazolon-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,

D(-)-α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

α-[(4-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylthio-benzylpenicillin,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)methylpenicillin,

α-[(5-methylimidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)methylpenicillin,

D(-)-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(4,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-methylthio-benzylpenicillin,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(5,5-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillinor

α-[(4,4-dimethylimidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin.

EXAMPLE 58

If, in the procedure of Example 45, theα-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methylphenylacetic acidused therein is replaced by 0.02 mol of:-

D(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxyphenylaceticacid,

L(+)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxyphenylaceticacid,

D,l-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxyphenylaceticacid,

D(-)-α-[imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-dichlorophenylaceticacid,

L(+)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-dichlorophenylaceticacid or

D,l-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-dichlorophenylaceticacid,

the following penicillins are obtained in the form of their sodiumsalts:-

D(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxy-benzylpenicillin,

L(+)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxy-benzylpenicillin,

D,l-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxy-benzylpenicillin,

D(-)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-dichlorobenzylpenicillin,

L(+)-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-dichlorobenzylpenicillinor

D,l-α-[(imidazolidin-2-on-1-yl)-carbonylamino]-o,o'-dichlorobenzylpenicillin.

Table 7

NMR data of some penicillins of the formula (1). Position of the signalsis indicated in the τ-scale [ppm]. Solvent: CD₃ OD.

    ______________________________________                                        Example                                                                              NMR signals at   Impurities visible in                                        [intensity of the signals,                                                                     the spectrum.                                                deducting the signals of                                                      the intermediate acid]                                                 ______________________________________                                        45     2.4-3.0 (4 H), 4.3-4.6                                                                         15% by weight of α-                                    (3 H) 5.8 (1 H), 5.9-6.4                                                                       (imidazolidin-2-on-1-yl-                                     (2 H), 6.4-6.9 (2 H), 7.7                                                                      carbonylamino)-p-methyl-                                     (3 H) and 8.4 (6 H)                                                                            phenylacetic acid                                     46     as Example 45    60% by weight of α-                                                     (imidazolidin-2-on-1-yl-                                                      carbonylamino)-p-methyl-                                                      phenylacetic acid                                     47     2.6 (4 H), 4.3-4.6 (3 H),                                                                      10% by weight of α-                                    5.8 (1 H), 5.9-6.8 (4 H)                                                                       (imidazolidin-2-on-1-                                        and 8.3-8.6 (6 H)                                                                              yl-carbonylamino)-p-                                                          chloro-phenylacetic                                                           acid                                                  48A    as Example 47    25% by weight of α-                                                     (imidazolidin-2-on-1-                                                         yl-carbonylamino)-p-                                                          chloro-phenylacetic                                                           acid                                                  48B    0.9 (1 H), 2.6 (2 H),                                                  acetone-                                                                             2.8 (3 H), 4.5 (1 H),                                                  d.sub.6 as the                                                                       6.2 (2 H), 6.6 (2 H),                                                                          --                                                    solvent                                                                              and 7.7 (3 H)                                                          48C    0.9 (1 H), 2.55 (4 H),                                                 acetone-                                                                             4.5 (1 H), 6.2 (2 H),                                                                          --                                                    d.sub.6 as the                                                                       and 6.5 (2 H)                                                          solvent                                                                       49     2.4-2.75 (5 H), 4.45-4.6                                                      (1 H), 6.0-6.85 (4 H)                                                                          --                                                    50     2.55-2.8 (4 H), 4.55-4.7                                                      (1 H), 5.95-6.8 (4 H),                                                                         --                                                           7.55 (3 H)                                                             51     2.35-2.75, 4.35-4.55, 5.75                                                                     58% by weight of D-                                          5.95-6.85, 8.3-8.55                                                                            α-(imidazolidin-2-                                                      on-1-yl-carbonyl-                                                             amino)-phenyl-acetic                                                          acid                                                  52     (free acid) 2.4-2.7 (5 H),                                                    4.3-4.6 (3 H), 5.55 (1 H),                                                    5.9-6.7 (4 H), 8.25-8.5                                                       (6 H) (Na salt) 2.45-2.75                                                                      --                                                           (5 H), 4.3-4.6 (3 H), 5.8                                                     (1 H), 5.95-6.75 (4 H),                                                       8.3-8.6 (6 H)                                                          54     2.45-2.9, 4.35-4.6, 5.8,                                                                       60% by weight of                                             5.9-6.85, 7.6, 8.3-8.55                                                                        α-(imidazolidin-2-                                                      on-1-yl-carbonyl-                                                             amino)-p-methyl-                                                              thio-phenylacetic                                                             acid                                                  55     2.4-2.9, 4.35-4.65, 5.8                                                                        40% by weight of                                             5.95-6.8, 7.6, 8.3-8.6                                                                         α-(imidazolidin-2-                                                      on-1-yl-carbonyl-                                                             amino)-p-methylthio-                                                          phenylacetic acid                                     ______________________________________                                    

EXAMPLE 59 Sodium D(-)-α-(3-benzoyl-3-methyl-ureido)-benzylpenicillin:

D(-)-α-Aminobenzylpenicillin (ampicillin) 15 parts by weight) wassuspended in 80% strength aqueous tetrahydrofurane (150 parts by volume)and sufficient triethylamine (approx. 7.5 parts by volume) was addeddropwise at 20°C, while stirring, that a clear solution was justproduced and the pH value was between 7.5 and 8.2 (glass electrode). Themixture was now cooled to 0°C and a solution ofN-benzoyl-N-methylcarbamic acid chloride (6.5 parts by weight) inabsolute tetrahydrofurane (25 parts by volume) was added dropwise overthe course of 30 minutes, while cooling with ice, the pH value beingkept between 7.5 and 8.0 through simultaneous addition of triethylamine.The mixture was stirred for 30 minutes at 0°C and subsequently furtherstirred at room temperature until addition of triethylamine was nolonger necessary for maintaining the pH value of 7.5. Water (150 partsby volume) was now added and the pH value was adjusted to 6.5 with alittle dilute surphuric acid, after which the tetrahydrofurane waslargely removed in a rotary evaporator at room temperature. The aqueoussolution which remained was extracted once by shaking with ether,subsequently covered with a 1:1 mixture of ethyl acetate and ether (400parts by volume) and treated with sufficient dilute sulphuric acid,while stirring and cooling with ice, to establish a pH value of 1 - 2.The organic phase was separated off, twice washed with water (60 partsby volume at a time) and dried at 0°C over MgSO₄ for about one hour, andafter filtering, the solution of the penicillin was treated with about50 parts by volume of a 1 molar solution of sodium 2-ethyl hexanoate inether containing methanol. The mixture was left to stand at 0°C for somehours, the solvent was subsequently decanted, and the residue wastriturated with ether and filtered off. After drying over P₂ O₅ in avacuum desiccator, the sodium salt of the penicillin was obtained in theform of a noncrystalline solid.

Yield: 14.7 parts by weight (83%). β-Lactam content: 87%.

    ______________________________________                                        Calculated:                                                                            C 55.4    H 4.8     N 10.3  S 5.9                                    Found:   C 56.2    H(7.0)    N  9.7  S 5.9                                    ______________________________________                                    

NMR signals at τ = 2.4 (10 H), 4.2 (1 H), 4.4 (2 H), 5.7 (1 H), 6.8 (3H) and 8.5 ppm (6 H).

Effectiveness against E. coli 14: 1.56 units/ml (6.25 units/ml^(x))

Effectiveness against Proteus 3400: 12.5 units/ml (50 units/ml^(x))

Effectiveness against Pseudomonas aerug. Bonn: 12.5 units/ml (25units/ml^(x))

The figures given in brackets give, for comparison, the particulareffectiveness of the corresponding penicillin which carries hydrogen inthe 3-position in the side chain (that is to say, which is not a subjectof the present invention; compare Netherlands Pat. No. 69/08909published Dec. 16, 1969), that is to say sodiumD(-)-α-(3-benzoylureido)benzylpenicillin.

Effectiveness in animal experiments: A and B.

EXAMPLE 60 Sodium D(-)-α-(3-benzoyl-3-ethyl-ureido)-benzylpenicillin:

This penicillin was prepared in the manner described in Example 59, from15 parts by weight of ampicillin and 7.0 parts by weight ofN-benzoyl-N-ethylcarbamic acid chloride.

Yield: (crude product): 79% β-Lactam content: 91%

    ______________________________________                                        Calculated:                                                                            C 53.8    H 5.4     N 9.6   S 5.6                                    Found:   C 53.0    H 5.0     N 9.9   S 5.7                                    ______________________________________                                    

NMR signals at τ = 2.5 (5 H), 2.6 (5 H), 4.5 (3 H), 5.8 (1 H), 6.2 (2H), 8.4 (6 H) and 8.8 ppm (3 H).

Effectiveness against E. coli 14: 6.25 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 61 SodiumD(-)-α-(3-ethoxycarbonyl-3-methyl-ureido)-benzylpenicillin:

If 18 parts by weight of ampicillin were reacted with 6.6 parts byweight of N-ethoxycarbonyl-N-methylcarbamic acid chloride in the mannerdescribed in Example 59, the penicillin was obtained in the form of itsNa salt, in 72% yield.

β-Lactam content: 94%

    ______________________________________                                        Calculated:                                                                            C 49.3    H 5.1     N 11.0  S 6.3                                    Found:   C 48.9    H 5.4     N 10.8  S 6.2                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (3 H), 6.8 (3H), 8.5 (6 H) and 8.7 ppm (3 H).

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 12.5 units/ml

Effectiveness in animal experiments: A and B.

EXAMPLE 62 SodiumD(-)-α-(3-hexahydrobenzoyl-3-methyl-ureido-benzylpenicillin:

On reacting 15 parts by weight of ampicillin with 6.7 parts by weight ofN-hexahydrobenzoyl-N-methylcarbamic acid chloride in accordance with theinstruction of Example 59, the sodium salt of the penicillin wasobtained in 60% yield.

β-Lactam content: 89%.

    ______________________________________                                        Calculated:                                                                            C 53.5    H 6.0     N 10.0  S 5.8                                    Found:   C 51.9    H 6.2     N 9.6   S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.5 (1 H), 4.55 (2 H), 5.8 (1 H), 6.7 (3H), 7.3 (1 H), 8.0-9.0 (10 H) and 8.5 ppm (6 H).

Effectiveness against Proteus 3400: 6.25 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 12 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 63 Sodium D(-)-α-(3-cinnamoyl-3-methyl-ureido)-benzylpenicillin:

The sodium salt of the penicillin was prepared from 15 parts by weightof ampicillin and 7.4 parts by weight of N-cinnamoyl-N-methylcarbamicacid chbride, as in Example 59.

Yield: 72% β-Lactam content: 90%

    ______________________________________                                        Calculated:                                                                            C 55.9    H 5.1     N 9.6   S 5.5                                    Found:   C 54.8    H 5.6     N 9.4   S 5.4                                    ______________________________________                                    

NMR signals at τ = 2.0-3.0 (12 H), 4.4 (1 H), 4.5 (1 H), 5.8 (1 H), 6.7(3 H), 8.4 (3 H) and 8.5 ppm (3 H).

Effectiveness against E. coli 14: <0.78 units/ml.

Effectiveness against Proteus 1017: 1.56 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 6.25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 64 Sodium D(-)-α-(3 -β-chloropropionyl-3-methyl-ureido)-benzylpenicillin:

19.7 parts by weight of ampicillin were reacted with 7.0 parts by weightof N-β-chloropropionyl-N-methylcarbamic acid chloride in accordance withExample 59.

Yield: 80% β-Lactam content: 94%

    ______________________________________                                        Calculated:                                                                            C 47.8   H 4.8    Cl 6.7 N. 10.6 S 6.1                               Found:   C 48.4   H 5.5    Cl 6.0 N 10.5  S 6.5                               ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.2 (2H), 6.8 (3 H), 6.9 (2 H) and 8.5 ppm (6 H)

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Proteus 1017: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 65 SodiumD(-)-α-(3-(1,2,5,6)-tetrahydrobenzoyl-3-methyl-ureido)benzylpenicillin:

This penicillin was prepared in the manner described in Example 59, from15.8 parts by weight of ampicillin and 7.0 parts by weight ofN-1,2,5,6-tetrahydrobenzoyl-N-methyl-carbamic acid chloride.

Yield: 55% β-Lactam content: 85% (according to the IR spectrum)

    ______________________________________                                        Calculated:                                                                            C 55.2    H 5.6     N 10.3  S 5.9                                    Found:   C 54.5    H 6.3     N 10.2  S 5.9                                    ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.2-4.6 (5 H), 5.8 (1 H) 6.7 (3 H),7.1 (1 H) and 7.6-8.8 ppm (12 H)

Effectiveness against E. coli 14: <0.78 units/ml.

Effectiveness against Proteus 1017: 3.12 units/ml.

Effectiveness against Pseudomonas Aerug. BOnn: 12.5 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 66A Sodium D(-)-α-(3-acetyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared in the manner described in Example 59, from20 parts by weight of ampicillin and 6.0 parts by weight ofN-acetyl-N-methyl-carbamic acid chloride.

Yield: 100% β-Lactam content: 86%

    ______________________________________                                        Calculated:                                                                            C 49.2    H 5.1     N 11.5  S 6.5                                    Found:   C 49.2    H(7.0)    N 10.4  S 6.5                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.45 (1 H), 4.55 (2 H), 5.8 (1 H), 6.75 (3H), 7.7 (3 H) and 8.5 ppm (6 H).

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 6.25 units/ml.

Effectiveness against Klebsiella K 10: 50 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 66B Crystalline sodiumD(-)-α-(3-acetyl-3-methyl-ureido)-benzylpenicillin:

The process of preparing sodiumD(-)-α-(3-acetyl-3-methylureido)-benzylpenicillin, following Example 59,yields an amorphous product, as is shown by an X-ray diffractionpicture. If this substance (3.8 parts by weight) is dissolved in ethanol(15 parts by volume) at room temperature (duration of the solutionprocess approximately 14 to 20 minutes), acetic acid ethyl ester (60parts by volume) is subsequently added, and the clear colorless solutionis left to stand at room temperature, very fine hair-like crystals(bundles of needles), which are recognizable as such with the naked eye,begin to separate out after 1 to 2 hours, if crystal seeds are not yetpresent. After some hours the crystals are filtered off, washed withacetic acid ethyl ester and dried thoroughly in a chamber wherein dryingis effected by circulating air at 60°C.

Yield: 3.0 parts by weight. β-Lactam content: 92%. Melting point: about212°C (corrected, decomposition) (Kofler bench). NMR signals at τ = 2.5(5 H), 4.4 (1 H), 4.55 (2 H), 5.8 (1 H), 6.7 (3 H), 7.7 (3 H) and 8.5ppm (6 H). Calculated: (1.9% H₂ O content C 50.1 H 5.0 N 11.7 S 6.7taken into account). Found: C 50.1 H 5.8 N 10.8 S 7.0.

The IR spectra of the amorphous and crystalline penicillin salt aredepicted in FIGS. 1 and 2.

It is however also possible to suspend the amorphous penicillin salt inacetic acid ethyl ester and then to add about 20% of ethanol whilestirring, In that case, also, a clear solution is produced, from whichthe crystalline penicillin salt separates out.

It is furthermore also possible to use other solvent mixtures, forexample ethanol/dioxane. If the amorphous salt is dissolved in acetoneor warm (approx. 50°C) isopropanol and left to stand, the salt againseparates out in a crystalline form.

EXAMPLE 67 SodiumD(-)-α-(3-cyclohexyloxycarbonyl-3-methyl-ureido)benzylpenicillin:

This penicillin was obtained from 20 parts by weight of ampicillin and12 parts by weight of N-cyclohexyloxycarbonyl-N-methylcarbamic acidchloride, in the manner described in Example 59.

Yield: 49%; β-Lactam content: 94%. Calculated: C 53.2 H 5.7 N 9.9 S 5.7.Found: C 53.1 H 6.5 N 9.7 S 5.5. NMR signals at τ = 2.6 (5 H), 4.4 (1H), 4.5 (2 H), 5.2 (1 H), 5.8 (1 H), 6.8 (3 H) and 7.9-8.9 (16 H).

Effectiveness against E. coli 14: 1.56 units/ml.

Effectiveness against Proteus 3400: 6.25 units/ml.

Effectiveness against Pseudonomas Aerug. Bonn: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 68 SodiumD(-)-α-(3-allyloxycarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 19.2 parts by weight of ampicillin and7.5 parts by weight of N-allyloxycarbonyl-N-methyl-carbamic acidchloride in the manner described in Example 59.

Yield: 79% β-Lactam content: 90%

    ______________________________________                                        Calculated:                                                                            C 50.9    H 5.0     N 10.7  S 6.2                                    Found:   C (53.8)  H 5.8     N 10.7  S 6.2                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 3.7-4.3 (1 H), 4.4 (1 H), 4.4-4.9 (4 H),5.2 (2 H), 5.8 (1 H), 6.8 (3 H) and 8.4 ppm (6 H).

Effectiveness against Pseudomonas Aerug. Bonn: 12.5 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 69 SodiumD(-)-α-(3-γ-trifluorobutyryl-3-methyl-ureido)-benzylpenicillin

This penicillin was obtained in the manner described in Example 59, onreacting 16.7 parts by weight of ampicillin with 8.0 parts by weight ofN-γ-trifluorobutyryl-N-methylcarbamic acid chloride.

Yield: 80% β-Lactam content: 91%

    ______________________________________                                        Calculated:                                                                            C 47.1    H 4.5     N 9.9   S 5.7                                    Found:   C 46.6    H 4.9     N 9.6   S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.4 (1 H), 4.55 (2 H), 5.8 (1 H), 6.9-7.8(4 H) and 8.5 ppm (6 H).

Effectiveness against E. coli 14: 1.56 units/ml.

Effectiveness against Proteus 1017: 12.5 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 12.5 units/ml.

Effectiveness against Klebsiella 63: 12.5 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 70 SodiumD(-)-α-(3-[m-nitro-p-methyl]-benzoyl-3-methyl-ureido)benzylpenicillin:

This penicillin was obtained in the manner described in Example 59, onreacting 15 parts by weight of ampicillin with 8.5 parts by weight ofN-m-nitro-p-methylbenzoyl-N-methylcarbamic acid chloride.

Yield: 64% β-Lactam content: 88%

    ______________________________________                                        Calculated:                                                                            C 50.7    H 4.7     N 11.3  S 5.2                                    Found:   C 50.6    H 5.7     N 11.2  S 5.0                                    ______________________________________                                    

NMR signals at τ = 1.9 (1 H), 2.2-2.4 (1 H), 2.4-2.8 (6 H), 4.4 (1 H),4.5 (2 H), 5.8 (1 H), 6.8 (3 H), 7.4 (3 H), and 8.5 ppm (6 H).

Effectiveness against Pseudomonas aerug. Bonn: 12.5 units/ml.

Effectiveness against Klebsiella 63: 12.5 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 71 SodiumD(-)-α-(3-stearinoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 15 parts by weight of ampicillin and11.9 parts by weight of N-stearinoyl-N-methyl-carbamic acid chloride inthe manner described in Example 59.

Yield: 80%. β-Lactam content: 80%

    ______________________________________                                        Calculated:                                                                            C 61.4    H 8.0     N 8.0   S 4.5                                    Found:   C 61.0    H 8.4     N 7.5   S 4.3                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.8 (3H), 7.4 (2 H), and 8.3-9.3 ppm (39 H).

EXAMPLE 72 SodiumD(-)-α-(3-γ-trichlorobutyryl-3-β-chloroethyl-ureido)benzylpenicillin:

This penicillin was prepared from 15 parts by weight of ampicillin and10.4 parts by weight of N-γ-trichlorobutyryl-N-β-chloroethyl-carbamicacid chloride in the manner described in Example 59.

Yield: 56%. β-Lactam content: 91%.

    ______________________________________                                        Calculated:                                                                            C 41.9   H 4.0    Cl 21.5 N 8.5 S 4.8                                         C 43.2   H 5.1    Cl 20.0 N 8.5 S 4.7                                ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H),5.8-7.2 (8H) and 8.5 ppm (6 H).

Effectiveness against E. coli 14: 6.25 units/ml.

Effectiveness against Klebsiella 63: 50 units/ml.

EFfectiveness in animal experiments: A and B.

EXample 73 SodiumD(-)-α-(3-p-methylbenzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 18 parts by weight of ampicillin and11 parts by weight of N-p-methylbenzoyl-N-methyl-carbamic acid chloridein the manner described in Example 59.

Yield: 79%. β-Lactam content: 89%.

    ______________________________________                                        Calculated:                                                                            C 55.4    H 5.2     N 9.9   S 5.7                                    Found:   C 54.6    H 6.7     N 9.9   S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.3-2.9 (9 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 6.85(3 H), 7.65 (3 H) and 8.45 (6 H).

Effectiveness against E. coli: 312 units/ml.

Effectiveness against Proteus 1017: 6.25 units/ml.

Effectiveness against Klebsiella 63: 12.5-25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 74 Sodium D(-)-α-(3-acetyl-3-hexadecyl-ureido)-benzylpenicillin:

This penicillin was prepared from 15 parts by weight of ampicillin and11.4 parts by weight of N-acetyl-N-hexadecylcarbamic acid chloride inthe manner described in Example 59.

Yield: 56% β-Lactam content: 76%

    ______________________________________                                        Calculated:                                                                            C 60.7    H 7.9     N 8.1   S 4.6                                    Found:   C 60.3    H 8.0     N 7.6   S 4.9                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.4 (1 H), 4.55 (2 H), 5.8 (1 H), 6.3 (2H), 7.7 (3 H), 8.45 (6 H), 8.7 (28 H), and 9.1 ppm (3 H).

EXAMPLE 75 SodiumD(-)-α-(3-thenoyl-(2)-3-methyl-ureido)-benzylpenicillin:

This penicillin was obtained in 81% yield on reacting 18.1 parts byweight of ampicillin with 8.2 parts by weight ofN-2-thenoyl-N-methyl-carbamic acid chloride. (See Example 59).

β-Lactam content: 92%

    ______________________________________                                        Calculated:                                                                            C 50.8    H 4.4     N 10.3  S 11.8                                   Found:   C 51.7    H 6.1     N 9.9   S 11.9                                   ______________________________________                                    

NMR signals at τ = 2.1-3.0 (8H), 4.4 (1H), 4.5 (1 H), 4.6 (1 H), 5.8 (1H), 6.6 (3 H) and 8.5 ppm (6 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 76 SodiumD(-)-α-[3,5-dimethylisoxazol-4-yl]-carbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 18.1 parts by weight of ampicillin and8.7 parts by weight ofN-4-(3,5-dimethyl)-isoxazolyl-carbonyl-N-methyl-carbamic acid chloride.(See Example 59).

Yield: 70% β -Lactam content: 85%

    ______________________________________                                        Calculated:                                                                            C 51.7    H 4.9     N 12.5  S 5.7                                    Found:   C 50.6    H 6.2     N 11.1  S 5.5                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.4 (1 H), 4.5 (1 H), 4.6 (1 H), 5.8 (1H), 6.8 (3 H), 7.6 (3 H), 7.75 (3 H), 8.4 (3 H) and 8.5 ppm (3 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 77

If, in the procedure of Examples 59 and 64, theD-α-amino-benzylpenicillin used there is replaced by 0.04 mol of:

α-amino-p-methylbenzylpenicillin,

α-amino-p-chlorobenzylpenicillin,

α-amino-p-methylthiobenzylpenicillin,

α-amino-p-methoxybenzylpenicillin,

α-amino-o-chlorobenzylpenicillin,

α-amino-m-iodobenzylpenicillin,

α-amino-2,6-dichlorobenzylpenicillin,

α-amino-2,6-dimethoxybenzylpenicillin,

α-amino-2,4-dibromobenzylpenicillin,

α-amino-m-methylbenzylpenicillin,

α-amino-2,6-dimethylbenzylpenicillin,

α-amino-2-chloro-6-fluorobenzylpenicillin,

α-amino-α-2-thienylmethylpenicillin or

α-amino-α-3-thienylmethylpenicillin;

the following penicillins are obtained:

sodium α-(3-benzoyl-3-methyl-ureido)-p-methylbenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-p-chlorobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-p-methylthiobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-p-methoxybenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-o-chlorobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-m-iodobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-2,6-dimethoxybenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-2,4-dibromobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-α-3-thienylmethylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-m-methylbenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-2,6-dimethylbenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-2-chloro-6-fluorobenzylpenicillin,

sodium α-(3-benzoyl-3-methyl-ureido)-α-2-thienylmethylpenicillin,

sodium α(3-acetyl-3-methyl-ureido)-p-methylbenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-p-chlorobenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-p-methylthiobenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-p-methoxybenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-o-chlorobenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-m-iodobenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-2,6-dichlorobenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-2,6-dimethoxybenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-2,4-dibromobenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-m-methylbenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-2,6-dimethylbenzylpenicillin,

sodium α-(3-acetyl-3-methyl-ureido)-2-chloro-6-fluorobenzylpenicillin,

sodium 60 -(3-acetyl-3-methyl-ureido)-α-2-thienylmethylpenicillin or

sodium α-(3-acetyl-3-methyl-ureido)-α-3-thienylmethylpenicillin.

EXAMPLE 78

If, in the procedure of Example 59, the N-benzoyl-N-methylcarbamic acidchloride used there is replaced by 0.035 mol of:

N-acetyl-N-ethyl-carbamic acid chloride,

N-acetyl-N-vinyl-carbamic acid chloride,

N-acetyl-N-n-propyl-carbamic acid chloride,

N-acetyl-N-propenyl-carbamic acid chloride,

N-acetyl-N-i-propyl-carbamic acid chloride,

N-acetyl-N-n-butyl-carbamic acid chloride,

N-acetyl-N-t-butyl-carbamic acid chloride,

N-acetyl-N-β-methoxyethyl-carbamic acid chloride,

N-acetyl-N-β-dimethylaminoethyl-carbamic acid chloride,

N-acetyl-N-cyclohexyl-carbamic acid chloride,

N-acetyl-N-cyclobutyl-carbamic acid chloride,

N-methoxyacetyl-N-methyl-carbamic acid chloride,

N-propionyl-N-methyl-carbamic acid chloride,

N-methyl-sulphenylacetyl-N-methyl-carbamic acid chloride,

N-propionyl-N-ethyl-carbamic acid chloride,

N-propionyl-N-vinyl-carbamic acid chloride,

N-n-butyryl-N-methyl-carbamic acid chloride,

N-methoxycarbonyl-acetyl-N-methyl-carbamic acid chloride,

N-i-butyryl-N-methyl-carbamic acid chloride,

N-acryloyl-N-methyl-carbamic acid chloride,

N-pivaloyl-N-methyl-carbamic acid chloride,

N-cyanomethyl-acetyl-N-methyl-carbamic acid chloride,

N-acetyl-N-phenyl-carbamic acid chloride or

N-propionyl-N-phenyl-carbamic acid chloride;

the following penicillins are obtained:

sodium D(-)-α-(3-acetyl-3-ethyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-vinyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-n-propyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-propenyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-i-propyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-n-butyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-t-butyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-β-methoxyethyl-ureido)-benzylpenicillin,

sodiumD(-)-α-(3-acetyl-3-β-dimethyl-aminoethyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-cyclohexyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-cyclobutyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-methoxyacetyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-propionyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-methylthio-acetyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-propionyl-3-ethyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-propionyl-3-vinyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-n-butyryl-3-methyl-ureido)-benzylpenicillin,

sodiumD(-)-α-(3-methoxycarbonyl-acetyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-i-butyryl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acryloyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-pivaloyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-cyano-methyl-acetyl-3-methyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-acetyl-3-phenyl-ureido)-benzylpenicillin or

sodium D(-)-α-(3-propionyl-3-phenyl-ureido)-benzylpenicillin.

EXAMPLE 79 Sodium D(-)-α-3-benzoyl-3-methyl-ureido)-benzylpenicillin:

A solution of 10.6 parts by weight of bis-trimethylsilylampicillin in 50parts by volume of dry methylene chloride was cooled to -10°C withexclusion of moisture, and treated with a solution of 3.8 parts byweight of N-benzoyl-N-methyl-carbamic acid chloride in 20 parts byvolume of absolute methylene chloride, cooled to 0°C. The mixture wasleft to stand in a refrigerator for 6 hours, the solvent was thenstripped off in a rotary evaporator at room temperature, the residue wastaken up in 100 parts by volume of a 1:1 mixture of ether and ethylacetate, and the solution was exhaustively extracted with 2N sodiumbicarbonate solution. The aqueous phase was treated with freshether-ethyl acetate mixture and acidified with 2 N HCl to pH = 1.5-2.0(glass electrode), while cooling with ice: the organic phase wasseparated off, again washed with water and subsequently dried over Na₂SO₄ at 0°C, and the sodium salt of the penicillin was precipitated, andisolated, in the manner described in Example 59.

Yield: 56%

β -Lactam content: 74%

    ______________________________________                                        Calculated:                                                                            C 54.1    H 5.0     N 10.1  S 5.8                                    Found:   C 54.0    H 5.6     N  9.5  S 5.7                                    ______________________________________                                    

The IR and NMR spectra are identical with those of the penicillin fromExample 1.

EXAMPLE 80 Sodium D(-)-α-(3-benzoyl-3-methyl-ureido)-benzylpenicillin:

15 parts by weight of ampicillin were suspended in 150 parts by volumeof 80% strength aqueous tetrahydrofurane and sufficient dilute HCL wassubsequently added, whilst cooling to -5°C, to establish a pH value of2.5 and partially to dissolve the ampicillin. A solution of 6.5 parts byweight of N-benzoyl-N-methyl-carbamic acid chloride in 25 parts byweight of absolute tetrahydrofurane was now added dropwise over thecourse of 30 minutes, at -5° to 0°C, while keeping the pH value at2.5-3.0 by simultaneous addition of triethylamine. The mixture wasstirred for a further 20 minutes until the pH value remained constant atabout 3.0 even without the addition of triethylamine. A pH value of6.5-7.0 was now established by means of triethylamine, 150 parts byvolume of water are added, and the tetrahydrofurane was evaporated offin a rotary evaporator at room temperature. The aqueous solution wasonce extracted with 100 parts by volume of ether, then covered with 200parts by volume of a 1:1 mixture of ether and ethyl acetate, and broughtto pH = 1.5-2.0 by adding 2 N hydrochloric acid whilst cooling with ice,and the penicillin was removed from the water by repeated extractionwith ether-ethyl acetate mixture. The combined organic phases were twicewashed with 100 parts by volume of water at a time and dried over MgSO₄,and the sodium salt of the penicillin was subsequently precipitated andisolated in the manner described in Example 59.

Yield: 60%.

β-Lactam content: 93.3%.

    ______________________________________                                        Calculated:                                                                            C 54.9    H 4.9     N 10.2  S 5.8                                    Found:   C 54.7    H 5.4     N 10.1  S 5.9                                    ______________________________________                                    

The product agrees with that of Example 1 in respect of its IR and NMRspectra.

EXAMPLE 81 SodiumD(-)-α-(3-γ-trichlorobutyryl-3-β-chloroethyl-ureido)benzylpenicillin:

A mixture of 8.0 parts by weight of ampicillin, 100 parts by volume ofmethylene chloride and 5.5 parts by volume of triethylamine was stirredfor 2 hours at room temperature, and then stirred vigorously, for afurther 15 minutes, with anhydrous sodium sulphate and filtered. Themixture was cooled to 0°C and a solution of 6.3 parts by weight ofN-γ-trichlorobutyryl-N-β-chloroethyl-carbamic acid chloride in 30 partsby volume of dry methylene chloride was added dropwise over the courseof 20 minutes, while excluding moisture. Thereafter the mixture wasstirred for a further 90 minutes at 0°C and then concentrated to drynessin a rotary evaporator, in vacuo. The residue was taken up in water, thepH value was adjusted to 7-8 with 2 N NaOH, and the mixture wasextracted once with ether. Thereafter working up took place as inExample 59 under acid conditions, and the sodium salt of the penicillinwas precipitated and isolated.

Yield: 49%.

β-Lactam content: 81%.

The product agrees with that of Example 14 as regards its IR and NMRspectrum.

EXAMPLE 82 Calcium L(+)-α-(3-benzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared as described in Example 59, but instead ofthe D-α-aminobenzylpenicillin used in Example 59, 0.35 part by weight ofL-α-amino-benzylpenicillin was reacted with 0.15 parts by weight ofN-benzoyl-N-methyl carbamic acid chloride. The penicillin was isolatedas the calcium salt.

Yield: 5%

β-Lactam content: 75%

NMR signals at τ = 2.4-2.8 (10 H), 4.35-4.65 (3H), 5.8 (1 H), 6.85 (3H)and 8.4 ppm (6 H).

EXAMPLE 83 SodiumD(-)-α-(3-[4-methoxy-3-nitrobenzoyl]-3-methyl-ureido)benzylpenicillin):

Sufficient 2 N NaOH was added to a suspension of 17.5 parts by weight ofampicillin in 250 parts by volume of 80% strength aqueoustetrahydrofurane, at 0°C, for solution just to occur. A solution of 13.6parts by weight of N-(4-methoxy-3-nitrobenzoyl)-carbamic acid chloridein 30 parts by volume of absolute tetrahydrofurane was now addeddropwise over the course of 30 minutes, and the pH value wassimultaneously kept between 7.5 and 8.0 by adding 2 N sodium hydroxidesolution. The mixture was stirred for a further 30 minutes at 0°C andsufficiently long (≠60 minutes) at room temperature for the pH value toremain at 7-8 even without addition of sodium hydroxide solution. Thetetrahydrofurane was now recovered in a rotary evaporator, at roomtemperature, 100 parts by volume of water were added and the mixture wasextracted with 100 parts by volume of ether. The aqueous phase wascovered with 200 parts by volume of a 1:1 mixture of ether and ethylacetate after which it was acidified to pH = 2 with dilute hydrochloricacid, while stirring and cooling with ice, and was then extracted twicewith 100 parts by volume, at a time, of ether-ethyl acetate mixture. Thecombined organic phases were washed with 2 × 50 parts by volume of waterand dried over anhydrous MgSO₄, the drying agent was filtered off, andthe filtrate was treated with 50 parts by volume of a molar solution ofsodium 2-ethylhexanoate in ether containing methanol. Thereafter, thesolvent was almost completely removed in vacuo at room temperature, theresidue was taken up in methanol, and the sodium salt of the penicillinwas precipitated by adding ether. After standing for 30 minutes at 0°C,the supernatant solvent was decanted, and the residue was suspended inether, filtered and dried over P₂ O₅ in a vacuum desiccator.

Yield: 88%.

β-Lactam content: 72%.

    ______________________________________                                        Calculated:                                                                            C 51.3    H 4.3     N 11.5  S 5.3                                    Found:   C 51.5    H 5.7     N 10.7  S 5.1                                    ______________________________________                                    

NMR signals at τ = 1.9 (1 H), 2,2 (1 H), 2.6 (5 H), 2.7 (1H), 4.4 (1 H),4.5 (2 H), 5.8 (1 H), 6.0 (3 H), 6.7 (3 H) and 8.45 ppm (6 H).

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Proteus 3400: 6.25 units/ml.

Effectiveness in animal experiments: A and B.

Example 84

If, in the procedure of Example 83, the ampicillin used there isreplaced by 0.05 mol of:

α-amino-p-methylbenzylpenicillin,

α-amino-p-chlorobenzylpenicillin,

α-amino-p-methoxybenzylpenicillin,

α-amino-p-methylsulphenylbenzylpenicillin,

α-amino-o-chlorobenzylpenicillin,

α-amino-m-iodobenzylpenicillin or

α-amino-m-methylbenzylpenicillin;

the following penicillins are obtained:

sodiumα-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-p-methylbenzylpenicillin,

sodiuma-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-p-chlorobenzylpenicillin,

sodiuma-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-p-methoxybenzylpenicillin

sodiumα-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-p-methylthiobenzylpenicillin,

sodiumα-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-o-chlorobenzylpenicillin,

sodiumα-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-m-iodobenzylpenicillinor sodiumα-(3-[3-nitro-4-methoxybenzoyl]-3-methyl-ureido)-m-methylbenzylpenicillin.

EXAMPLE 85

If, in the procedure according to Example 83, theN-(3-nitro-4-methoxybenzoyl)-N-methyl-carbamic acid chloride used thereis replaced by 0.05 mol of:

N-(p-methoxybenzoyl)-N-methyl-carbamic acid chloride,

N-(p-methoxycarbonylaminobenzoyl)-N-methyl-carbamic acid chloride,

N-(p-chlorobenzoyl)-N-ethyl-carbamic acid chloride,

N-(o-bromobenzoyl)-N-(n-propyl)-carbamic acid chloride,

N-(p-ethoxybenzoyl)-N-(i-propyl)-carbamic acid chloride,

N-(m-chlorobenzoyl)-N-allyl-carbamic acid chloride,

N-(2-chloro-5-methoxy-benzoyl)-N-(n-butyl)-carbamic acid chloride,

N-(p-methylthiobenzoyl)-N-methyl-carbamic acid chloride,

N-(p-nitrobenzoyl)-N-methyl-carbamic acid chloride,

N-(2,4-dichlorobenzoyl)-N-methyl-carbamic acid chloride,

N-(2-chloro-4-methoxybenzoyl)-N-methyl-carbamic acid chloride,

N-(2-chloro-4-ethylthiobenzoyl)-N-methyl-carbamic acid chloride,

N-(3-chloro-4-methoxybenzoyl)-N-methyl-carbamic acid chloride,

N-(m-cyanobenzoyl)-N-methyl-carbamic acid chloride,

N-(3,5-dimethylbenzoyl)-N-methyl-carbamic acid chloride,

N-(m-iodobenzoyl)-N-methyl-carbamic acid chloride or

N-(1-naphthoyl)-N-methyl-carbamic acid chloride;

The sodium salts of the following penicillins are obtained:

D(-)-α-(3-p-methoxybenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-methoxycarbonylaminobenzoyl)-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-chlorobenzoyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-o-bromobenzoyl-3-n-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-ethoxybenzoyl-3-i-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-m-chlorobenzoyl-3-allyl-ureido)-benzylpenicillin,

D(-)-α-(3-[2-chloro-5-methoxybenzoyl]-3-n-butyl-ureido)-benzylpencillin,

D(-)-α-(3-p-methylthiobenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-p-nitrobenzoyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[2,4-dichlorobenzoyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[2-chloro-4-methoxybenzoyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[2-chloro-4-ethylthiobenzoyl]-3-methyl-ureido)benzylpenicillin,

D(-)-α-(3-[3-chloro-4-methoxybenzoyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-m-cyanobenzoyl- 3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[3,5-dimethylbenzoyl]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-m-iodobenzoyl-3 -methyl-ureido)-benzylpenicillin or

D(-)-α-(3-[i-naphthoyl]-3-methyl-ureido)-benzylpenicillin.

EXAMPLE 86 Sodium D(-)-α-(3-acetyl-3-allyl-ureido)-benzylpenicillin:

This penicillin was prepared in the manner described in Example 83, byreacting 17.5 parts by weight of ampicillin with 8.1 parts by weight ofN-acetyl-N-allyl-carbamic acid chloride.

Yield: 81%.

β-Lactam content: 82%.

    ______________________________________                                        Calculated:                                                                            C 51.2    H 5.3     N 10.8  S 6.2                                    Found:   C 51.9    H(6.9)    N 10.5  S 6.4                                    ______________________________________                                    

NMR signals at τ = 2.4-2.8 (5 H), 4.5-5.2 (6 H), 5.6 (2 H), 5.85 (1 H),7.7 (3 H) and 8.5 ppm (6 H).

Effectiveness against E. coli 14: 12.5 units/ml.

Effectiveness against Pseudomonas Aerug. Bonn: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 87 Sodium D(-)-α-(3-acetyl-3-allyl-ureido)-benzylpenicillin:

This penicillin was prepared from 17.5 parts by weight of ampicillin and10.6 parts by weight of N-acetyl-N-benzyl carbamic acid chloride, in themanner described in Example 83.

Yield: 85%.

β-Lactam content: 70%.

    ______________________________________                                        Calculated:                                                                            C 54.4    H 5.3     N 9.77  S 5.7                                    Found:   C 54.4    H 5.7     N 9.77  S 5.6                                    ______________________________________                                    

NMR signals at τ = 2.3-3.0 (10 H), 4.4 (1 H), 4.5 (2 H), 5.0 (2 H), 5.8(1 H), 7.8 (3 H) and 8.5 (6 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 88 SodiumD(-)-α-(3-γ-chlorobutyryl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 17.5 parts by weight of ampicillin and9.9 parts by weight of N-γ-chlorobutyryl-N-methylcarbamic acid chloride,in the manner described in Example 83.

Yield: 91%.

β-Lactam content: 67%.

    ______________________________________                                        Calculated:                                                                            C 49.6   H 4.9    Cl 6.6 N 10.5 S 6.0                                Found:   C 49.8   H 6.1    Cl 6.1 N 10.3 S 6.5                                ______________________________________                                    

NMR signals at τ = 2.3-2.9 (5 H), 4.45 (1 H), 4.55 (2 H), 5.8 (1 H), 6.4(2 H), 6.75 (3 H), 7.3 (2 H), 7.9 (2 H) and 8.5 ppm (6 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 89 SodiumD(-)-α-(3-γ-trichlorobutyryl-3-methyl-ureido)-benzylpenicillin

This penicillin was prepared from 17.5 parts by weight of ampicillin and13.4 parts by weight of N-γ-trichlorobutyryl-N-methyl-carbamic acidchloride, in the manner described in Example 83.

Yield: 77%.

β-Lactam content: 66.5%.

    ______________________________________                                        Calculated:                                                                            C 43.9   H 4.0    Cl 17.7                                                                              N 9.3  S 5.3                                Found:   C 44.5   H 5.6    Cl 15.4                                                                              N 8.2  S 5.3                                ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1 H), 4.55 (2 H), 5.8 (1 H), 6.7(4 H), 6.9 (3 H) and 8.45 ppm (6 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 90 Sodium D(-)-α-(3-benzoyl-3-allyl-ureido)-benzylpenicillin:

This penicillin was prepared from 17.5 parts by weight of ampicillin and11.2 parts by weight of N-benzoyl-N-allylcarbamic acid chloride, in themanner described in Example 83.

Yield: 75%.

β-Lactam content: 90%.

    ______________________________________                                        Calculated:                                                                            C 56.0    H 4.8     N 10.9  S 5.7                                    Found:   C 56.1    H 5.6     N  9.7  S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.5 (5 H), 2.6 (5 H), 4.3-5.0 (6 H), 5.65 (2 H), 5.8(1 H), 8.5 (6 H).

Effectiveness against E. coli 14: 6.25 units/ml.

Effectiveness against Proteus 1017: 12.5 units/ml.

Effectiveness against Klebsiella 63: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 91 SodiumD(-)-α-(3-[2-furoyl]-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 35 parts by weight of ampicillin and15 parts by weight of N-2-furoyl-N-methylcarbamic acid chloride, in themanner described in Example 83.

Yield: 83%.

β-Lactam content: 85%.

    ______________________________________                                        Calculated:                                                                            C 52.7    H 4.4     N 10.7  S 6.1                                    Found:   C 52.8    H 5.4     N  9.8  S 6.1                                    ______________________________________                                    

NMR signals at τ = 2.3 (1 H), 2.3-2.9 (6 H), 3.4 (1 H), 4.3 (1 H), 4.5(2 H), 5.7 (1 H), 6.6 (3 H) and 8.5 ppm (6 H).

EXAMPLE 92 (A) N-2-Furoyl-N-n-propyl-carbamic acid chloride:

This substance can be prepared according to the data in the literature,but especially according to the following process:

A solution of 7.6 parts by weight of 2-furanecarboxylicacid-N-n-propylamide in a 2:1 mixture of ether and tetrahydrofurane (150parts by volume), which had shortly before been distilled from LiAlH₄,was saturated with dry nitrogen and cooled to -30°C. 28.3 parts byvolume of a 1.765 M solution of CH₃ Li in ether was added dropwisethereto under a nitrogen atmosphere over the course of 30 minutes, whileexcluding moisture and stirring vigorously. The mixture was stirred fora further 15 minutes at -30°C. The resulting suspension was added from acooled dropping funnel, so that it did not rise above -10°C, to amixture, at -10°C, of 50 parts by volume of phosgene and 50 parts byvolume of absolute tetrahydrofurane, over the course of 1 hour. Themixture was allowed to come to room temperature after 15 minutes andstirred for a further 30 minutes, and the excess phosgene and thesolvents were then stripped off in vacuo. The LiCl, which very largelyremained undissolved, could substantially be separated off by suspendingin benzene. The residue which remained after distilling off the benzenecould be employed directly for the preparation of the penicillin. Itcould however also be distilled at 105°-112°C and 0.7 mm Hg. Yield 64%.In addition to the desired N-furoyl-N-propyl-carbamic acid chloride, theproduct also contained a further component, which however provided notto interfere in the subsequent preparation of the penicillin.

(B) Sodium D(-)-α-(3-[2-furoyl]-3-n-propyl-ureido)-benzylpenicillin:

This penicillin was prepared from 10.5 parts by weight of ampicillin and6.5 parts by weight of distilled N-2-furoyl-N-n-propylcarbamic acidchloride, in the manner described in Example 83.

Yield: 30%.

β-Lactam content: 90%.

NMR signals at τ = 2.35 (1 H), 2.6 (5 H), 2.8 (1 H), 3.4 (1 H), 4.4 (1H), 4.5 (2 H), 5.8 (1 H), 6.2 (2 H), 8.1-8.9 (1 H), 8.5 (6 H) and 9.1ppm (3 H).

EXAMPLE 93 (A) N-2-Furoyl-N-ethyl-carbamic acid chloride:

This substance was prepared from 7.0 parts by weight of2-furanecarboxylic acid-N-ethylamide, CH₃ Li and phosgene, in the mannerdescribed in Example 92-A.

Boiling point₁.5 = 90° - 95°C. Yield: 80% (crude product).

The substance contains a second component, which however proved not tointerfere in the preparation of the penicillin.

(B) Sodium D(-)-α-(3-[2-furoyl]-3-ethyl-ureido)-benzylpenicillin:

This penicillin was prepared from 12 parts by weight of ampicillin and 7parts by weight of N-2-furoyl-N-ethyl-carbamic acid chloride, in themanner described in Example 83.

Yield: 29%. β-Lactam content: 89%.

    ______________________________________                                        Calculated:                                                                            C 52.8      H 4.6       N 10.7                                       Found:   C 52.6      H(6.2)      N  9.7                                       ______________________________________                                    

NMR signals at τ = 2.3 (1 H), 2.6 (5H), 2.75 (1 H), 3.4 (1 H), 4.35 (1H), 4.5 (2 H), 5.8 (1 H), 6.05 (2 H), 8.45 (6 H) and 8.7 ppm (3 H).

EXAMPLE 94 SodiumD(-)-α-(3-dimethylaminocarbonyl-3-methyl-ureido)benzylpenicillin:

This penicillin was prepared from 17.5 parts by weight of ampicillin and7.8 parts by weight of N-dimethylaminocarbonyl-N-methyl-carbamic acidchloride, in the manner described in Example 83.

Yield: 74%. β-Lactam content: 82%.

    ______________________________________                                        Calculated:                                                                            C 49.6    H 5.4     N 13.8  S 6.3                                    Found:   C 49.9    H 6.4     N 13.1  S 6.0                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.5 (3 H), 5.8 (1 H), 6.95 (3 H), 7.05 (6H) and 8.45 ppm (6 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 95

If the N-dimethylaminocarbonyl-N-methyl-carbamic acid chloride used inExample 94 is replaced by:

3-dimethylaminocarbonyl-3-ethyl-carbamic acid chloride,

3-dimethylaminocarbonyl-3-propyl-carbamic acid chloride,

3-dimethylaminocarbonyl-3-i-propyl-carbamic acid chloride,

3-dimethylaminocarbonyl-3-n-butyl-carbamic acid chloride,

3-dimethylaminocarbonyl-3-allyl-carbamic acid chloride,

3-dimethylaminocarbonyl-3-cyclohexyl-carbamic acid chloride,

3-dimethylaminocarbonyl-3-phenyl-carbamic acid chloride,

N-(1-pyrrolidylcarbonyl)-N-methyl-carbamic acid chloride,

N-(1-piperidylcarbonyl)-N-methyl-carbamic acid chloride,

N-diethylaminocarbonyl-N-methyl-carbamic acid chloride,

N-ethylaminocarbonyl-N-methyl-carbamic acid chloride,

N-methylaminocarbonyl-N-methyl-carbamic acid chloride,

N-phenylaminocarbonyl-N-methyl-carbamic acid chloride,

N-(4-morpholinyl-carbonyl)-N-methyl-carbamic acid chloride,

N-(1-pyrrolidyl-carbonyl)-N-ethyl-carbamic acid chloride,

N-(1-piperidylcarbonyl)-N-ethyl-carbamic acid chloride,

N-diethylaminocarbonyl-N-ethyl-carbamic acid chloride,

N-ethylaminocarbonyl-N-ethyl-carbamic acid chloride

N-methylaminocarbonyl-N-ethyl-carbamic acid chloride,

N-phenylaminocarbonyl-N-ethyl-carbamic acid chloride,

N-(4-morpholinylcarbonyl)-N-ethyl-carbamic acid chloride,

N-(1-pyrrolidylcarbonyl)-N-n-propyl-carbamic acid chloride,

N-(1-piperidylcarbonyl)-N-i-propyl-carbamic acid chloride,

N-diethylaminocarbonyl-N-n-butyl-carbamic acid chloride or

N-dimethylaminocarbonyl-N-cyclohexyl-carbamic acid chloride,

the following penicillins are obtained in the form of their sodiumsalts:

D(-)-α-(3-dimethylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-i-propyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-n-butyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-allyl-ureido)-benzylpenicillin,

D(-)-α-(3-dimethylaminocarbonyl-3-cyclohexyl-ureido)-benzylpenicillin

D(-)-α-(3-dimethylaminocarbonyl-3-phenyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-pyrrolidyl]-carbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-piperidyl]-carbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-diethylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-ethylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-methylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-phenylaminocarbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[4-morpholinyl]-carbonyl-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-pyrrolidyl]-carbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-[1-piperidyl]-carbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-diethylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-ethylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-methylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-phenylaminocarbonyl-3-ethyl-ureido)-benzylpenicillin,

D(-)-α-(3-[4-morpholinyl]-carbonyl-3-ethyl-ureido)-benzylpencillin,

D(-)-α-(3-[1-pyrrolidyl]-carbonyl-3-n-propyl-ureido)-benzylpenicillin

D(-)-α-(3-[1-piperidyl]-carbonyl-3-i-propyl-ureido)-benzylpencillin,

D(-)-α-(3-diethylaminocarbonyl-3-n-butyl-ureido)-benzylpenicillin

D(-)-α-(3-dimethylaminocarbonyl-3-cyclohexyl-ureido)-benzylpenicillin

EXAMPLE 96 SodiumD(-)-α-(3-methoxycarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 24.5 parts by weight of ampicillin and10.2 parts by weight of N-methoxycarbonyl-N-methylcarbamic acidchloride, in the manner described in Example 83.

Yield: 84%. β-Lactam content: 84%.

    ______________________________________                                        Calculated:                                                                            C 47.6    H 5.0     N 11.1  S 6.4                                    Found:   C 48.4    H 5.5     N 10.6  S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.3-2.9 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.2(3 H), 6.8 (3 H) and 8.45 ppm (6 H).

Effectiveness against E. coli 14: 6.25 units/ml.

Effectiveness against Pseudomonas aerug. Bonn: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 97 SodiumD(-)-α-(3-i-propoxycarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 24.4 parts by weight of ampicillin and12.2 parts by weight of N-i-propoxycarbonyl-N-methyl-carbamic acidchloride, in the manner described in Example 83.

Yield: 72%. β-Lactam content: 88%.

    ______________________________________                                        Calculated:                                                                            C 51.3    H 5.3     N 10.9  S 6.2                                    Found:   C 51.6    H 5.5     N 10.6  S 6.1                                    ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.4 (1 H), 4.5 (2 H), 5.0 (1 H), 5.8(1 H), 6.85 (3 H), 8.5 (6 H) and 8.7 ppm (6 H).

Effectiveness against E. coli 14: 6.25 units/ml.

Effectiveness against Proteus 3400: 25 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 98 SodiumD(-)-α-(3-n-butoxycarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 24.5 parts by weight of ampicillin and13.6 parts by weight of N-n-butoxycarbonyl-N-methyl-carbamic acidchloride, in the manner described in Example 83.

Yield: 63%. β-Lactam content: 78%.

    ______________________________________                                        Calculated:                                                                            C 52.2    H 5.5     N 10.6  S 6.0                                    Found:   C 52.2    H 5.5     N 10.7  S 6.0                                    ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.45 (1 H), 4.55 (2 H), 5.8 (3 H),6.85 (3 H) and 8.1-9.3 ppm (13 H).

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Proteus 1017: 12.5 units/ml.

Effectiveness against Pseudomonas aerug. Bonn: 12.5 units/ml.

Effective in animal experiments: A and B.

EXAMPLE 99 (A) N-Benzoyl-N-phenyl-carbamic acid chloride:

This substance was obtained from 19.7 parts by weight of benzoylanilideby reaction with CH₃ Li and phosgene, in the manner described in Example92-A. Instead of distilling, the product was recrystallized frombenzene-petroleum ether.

Yield: 90%. Melting point 64° - 66°C.

(B) Sodium D(-)-α-(3-benzoyl-3-phenyl-ureido)-benzylpenicillin:

The triethylamine salt was prepared from 11.5 parts by weight ofampicillin in methylene chloride, as described in Example 81. Instead ofanhydrous sodium sulphate, 4 parts by weight of powdered Zeolite VS 10 -2 molecular sieve, added from the start, were used. Reaction with 7.8parts by weight of N-benzoyl-N-phenylcarbamic acid chloride, asdescribed in Example 81, though with the addition of a further 2.0 partsby weight of triethylamine to the reaction solution, yielded thispenicillin.

Yield: 72% β-Lactam content: 88%

    ______________________________________                                        Calculated:                                                                            C 57.9    H 4.8     N 9.0   S 5.4                                    Found:   C 57.7    H 5.4     N 9.0   S 6.3                                    ______________________________________                                    

NMR signals at τ = 2.4-2.9 (15 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 8.4and 8.5 ppm (6 H).

Effectiveness in animal experiments: B.

EXAMPLE 100D(-)-α-(3-[3-Nitro-4-methoxy-benzoyl]-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 7.0 parts by weight ampicillin and 5.5parts by weight of N-(3-nitro-4-methoxybenzoyl)-N-methylcarbamic acidchloride, in the manner described in Examples 81 and 99-B.

Yield: 77%. β-Lactam content: 89%.

    ______________________________________                                        Calculated:                                                                            C 48.5    H 4.7     N 10.9  S 5.0                                    Found:   C 48.4    H 5.4     N 10.8  S 5.4                                    ______________________________________                                    

The substance agrees with that of Example 83 as regards its IR and NMRspectrum.

EXAMPLE 101 (A) 1-Chlorocarbonyl-hexahydroazepin-2-one:

The substance was prepared from 6.8 parts by weight of ε-caprolactam andCH₃ Li and phosgene, in the manner described in Example 92-A.

Boiling point₀.2 = 80° - 85°C. Yield: 37% of pure material.

(B) SodiumD(-)-α-(hexahydroazepin-2-on-1-yl-carbonyl-amino)benzylpenicillin:

This penicillin was prepared from 8.1 parts by weight of ampicillin and4 parts by weight of 1 -chlorocarbonylhexahydroazepin-2-one, in themanner described in Examples 81 and 99-B.

Yield: 40% β-Lactam content: 90% NMR signals at τ = 2.6 (5 H), 4.3-4.6(3 H), 5.8 (1 H), 6.2-6.6 (2 H), 7.5-8.0 (2 H) and 8.0-8.9 ppm (12 H).

EXAMPLE 102 SodiumD(-)-α-(pyrrolid-2-on-1-yl-carbonylamino)-benzylpenicillin:

This substance was prepared from 35 parts by weight of ampicillin and 15parts by weight of 1-chlorocarbonylpyrrolidone, in the manner describedin Example 83.

Yield: 83% β-Lactam content: 70% NMR signals at τ = 2.6 (5 H), 4.4 (1H), 4.55 (2 H), 5.8 (1 H), 6.25 (2 H), 7.4 (2 H), 8.0 (2 H) and 8.5 ppm(6 H).

EXAMPLE 103 Sodium D(-)-α-(3-formyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 35 parts by weight of ampicillin and12.2 parts by weight of N-formyl-N-methylcarbamic acid chloride, in themanner described in Examples 81 and 99-B.

Yield: 25% β-Lactam content: 83%

EXAMPLE 104

If the N-formyl-N-methylcarbamic acid chloride used in Example 103 isreplaced by:

N-formyl-N-ethylcarbamic acid chloride,

N-formyl-N-propylcarbamic acid chloride,

N-formyl-N-i-propylcarbamic acid chloride,

N-formyl-N-n-butylcarbamic acid chloride,

N-formyl-N-allylcarbamic acid chloride,

N-formyl-N-benzylcarbamic acid chloride,

N-formyl-N-phenylcarbamic acid chloride,

N-formyl-N-cyclopropylcarbamic acid chloride,

N-formyl-N-cyclobutylcarbamic acid chloride

N-formyl-N-cyclopentylcarbamic acid chloride or

N-formyl-cyclohexylcarbamic acid chloride;

the following penicillins are obtained in the form of their sodiumsalts:

sodium D(-)-α-(3-formyl-3-ethyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-propyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-i-propyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-formyl-3-n-butyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-allyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-benzyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-phenyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-cyclopropyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-cyclobutyl-ureido)-benzylpenicillin,

sodium D(-)-α-(3-formyl-3-cyclopentyl-ureido)-benzylpenicillin and

sodium D(-)-α-(3-formyl-3-cyclohexyl-ureido)-benzylpenicillin.

EXAMPLE 105 (A) N-2-Furoyl-N-phenylcarbamic acid chloride:

The substance was prepared from 9.4 parts by weight of 2-furoylanilideby reaction with CH₃ Li and phosgene, in the manner described in Example101-A.

Crude yield: 95%.

The product was reacted, without further purification, to give thepenicillin of Example 104-B.

(B) Sodium D(-)-α-(3-[2-furoyl]-3-phenyl-ureido)-benzylpenicillin:

This penicillin was prepared from 16.2 parts by weight of ampicillin and11.5 parts by weight of N-2-furoyl-N-phenylcarbamic acid chloride, inthe manner described in Example 83.

Yield: 50%. β-Lactam content: 91%. NMR signals at τ = 2.4 (1 H), 2.5 (11H), 3.7 (1 H), 4.3-4.7 (3 H), 5.8 (1 H) and 8.45 ppm (6 H).

EXAMPLE 106

If, instead of the N-2-furoyl-N-phenylcarbamic acid chloride used inExample 105, 0.03 mol of:

N-(2,5-dimethyl-fur-3-oyl)-N-methylcarbamic acid chloride,

N-(5-bromo-fur-3-oyl)-N-methylcarbamic acid chloride,

N-(5-methoxymethylfur-2-oyl)-N-methylcarbamic acid chloride or

N-3,5-(dimethylisothiazol-3-yl-carbonyl)-N-methylcarbamic acid chloride

are reacted with ampicillin, the sodium salts of the followingpenicillins are obtained:

D(-)-α-(3-[2,5-dimethyl-furoyl-(3)]-3-methyl-ureido-benzylpenicillin,

D(-)-α-(3-[5-bromo-furoyl-(3)]-3-methyl-ureido)-benzylpenicillin,

D(-)-α-(3-[5-methoxymethyl-furoyl-(2)]-3-methyl-ureido)-benzylpenicillinor

D(-)-α-(3-[3,5-dimethylisothiazole-3-yl-carbonyl]-3-methyl-ureido)-benzylpenicillin.

EXAMPLE 107 SodiumD(-)-α-(3-o-chlorobenzoyl-3-methyl-ureido-benzylpenicillin:

16.2 parts by weight of N-o-chlorobenzoyl-N-methylcarbamic acid chlorideand 5 parts by weight of triethylamine were added at -10°C to a solutionof the triethylamine salt of 28 parts by weight of ampicillin in 300parts by volume of methylene chloride, the mixture was stirred, withexclusion of moisture, for 30 minutes at this temperature, andsubsequently for a further 2 hours at 0°C, and was then poured into icewater, and the pH was adjusted to 6.5. Thereafter, the organic phase wasseparated off, and the aqueous phase was covered with ether/ethylacetate mixture and adjusted to pH = 1.5-2.0 with dilute hydrochloricacid, while cooling with ice. After having separated off the organicphase and again having extracted the water with ether/ethyl acetatemixture, the combined organic solutions were dried over MgSO₄ andfiltered, and about 70 parts by volume of a 1 molar solution of sodium2-ethylhexanoate in ether containing methanol were added to thefiltrate. The mixture was evaporated almost to dryness in vacuo, theresidue was dissolved in methanol, and the product was precipitated as anon-crystalline, white solid substance by adding ether.

Yield: 26 %. β-Lactam content: 81%.

    ______________________________________                                        Calculated:                                                                            C 51.3    H 4.5     Cl 6.1  N 9.6                                    Found:   C 51.4    H 5.9     Cl 5.6  N 9.0                                    ______________________________________                                    

NMR signals at τ = 2.3-2.8 (9 H), 4.3 (1 H), 4.5 (2 H), 5.8 (1 H), 6.95(3 H) and 8.5 ppm (6 H).

Effectiveness in animal experiments: A and B

Effectiveness in animal experiments against Pseudomonas aerug. Walter:better than carbenicillin.

EXAMPLE 108 SodiumD(-)-α-(3-[3-nitro-4-methoxy-benzoyl]-3-ethyl-ureido)-benzylpenicillin:

This penicillin was prepared from 14.8 parts by weight of ampicillin and12.2 parts by weight of N-(3-nitro-4-methoxybenzoyl)-N-ethyl-carbamicacid chloride, as described in Example 107.

Yield: 24% β-Lactam content: 86%

    ______________________________________                                        Calculated:                                                                            C 49.2    H 4.9     N 10.6  S 4.9                                    Found:   C 49.2    H 5.3     N 10.1  S 5.5                                    ______________________________________                                    

NMR signals at τ = 2.0 (1 H), 2.3 (1 H), 2.4-2.9 (6 H), 4.5 (3 H), 5.9(1 H), 6.1 (3 H), 6.2 (2 H), 8.3-9.0 ppm (9 H).

Effectiveness in animal experiments: A and B

EXAMPLE 109 SodiumD(-)-α-(3-[3-nitro-4-methoxybenzoyl]-3-n-propylureido)-benzylpenicillin:

This penicillin was prepared from 21 parts by weight of ampicillin and18 parts by weight of N-(3-nitro-4-methoxybenzoyl)-N-n-propyl-carbamicacid chloride, in the manner described in Example 107.

Yield: 16%. β-Lactam content: 90%. NMR signals at τ = 2.0 (1 H), 2.3 (1H), 2.5-3.0 (6 H), 4.45 (1 H), 4.55 (2 H), 5.8 (1 H), 6.05 (3 H),6.1-6.6 (2 H) and 8.45-9.1 ppm (11 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 110 SodiumD(-)-α-(3-methylaminocarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and10.5 parts by weight of N-methylaminocarbonyl-N-methyl-carbamic acidchloride, in the manner described in Example 107.

Yield: 92%. β-Lactam content: 93%.

    ______________________________________                                        Calculated:                                                                            C 48.6    H 5.1     N 14.1  S 6.5                                    Found:   C 49.0    H 6.3     N 12.6  S 6.9                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.45 (1 H), 4.5 (2 H), 5.8 (1 H), 6.8 (3H), 7.2 (3 H) and 8.4 ppm (6 H).

Effectiveness in animal experiments: B.

EXAMPLE 111 SodiumD(-)-α-(3-[2,5-dichlorobenzoyl]-3-methyl-ureido)benzylpenicillin:

This penicillin was prepared from 28 parts by weight of ampicillin and18.7 parts by weight of N-(2,5-dichlorobenzoyl)-N-methylcarbamic acidchloride, in the manner described in Example 107.

Yield: 32%. β-Lactam content: 85%.

    ______________________________________                                        Calculated:                                                                            C 47.6    H 4.2     Cl 11.1 N 8.8                                    Found:   C 48.0    H(6.0)    Cl  9.7 N 8.6                                    ______________________________________                                    

NMR signals at τ = 2.3-2.8 (8 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 6.9(3 H), 8.4 (3 H) and 8.5 ppm (3 H).

EXAMPLE 112 SodiumD(-)-α-(3-p-chlorobenzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 28 parts by weight of ampicillin and16 parts by weight of N-p-chlorobenzoyl-N-methylcarbamic acid chloride,in the manner described in Example 107.

Yield: 16%

β-Lactam content: 82%

    ______________________________________                                        Calculated:                                                                            C 51.3   H 4.5    Cl 6.1 N 9.5  S 5.5                                Found:   C 51.9   H 5.6    Cl 5.4 N 9.1  S 5.5                                ______________________________________                                    

NMR signals at τ = 2.3-2.8 (9 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 6.95(3 H), 8.4 (3 H) and 8.5 ppm (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 113. SodiumD(-)-α-(3-propionyl-3-methyl-ureido)-benzylpenicillin:

6.0 parts by weight of N-propionyl-N-methyl-carbamic acid chloride in 25parts by volume of absolute tetrahydrofurane were added dropwise, at0°C, to a solution of 18 parts by weight of ampicillin in 180 parts byvolume of 80% strength aqueous tetrahydrofurane (pH = 8.2 adjusted withtriethylamine), while keeping the pH at 7-8 by adding triethylamine.Thereafter the mixture was further stirred at 0°C until no moretriethylamine had to be added to maintain the pH at 7 (about 15minutes). Water was now added, the tetrahydrofurane was stripped off invacuo, the residue was extracted once with ether/ethyl acetate mixture,and the aqueous phase was covered with fresh ether/ethyl acetatemixture. Thereafter a pH of 1.5-2.0 was established by adding dilutehydrochloric acid at 0°C, whereupon the mixture was worked up as inExample 107, and the penicillin was precipitated as the sodium salt.

Yield: 85%.

β-Lactam content: 91%.

    ______________________________________                                        Calculated:                                                                            C 51.1    H 5.3     N 11.3  S 6.5                                    Found:   C 51.2    H 6.4     N 11.1  S 7.5                                    ______________________________________                                    

NMR signals at τ = 2.3 -2.8 (5H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.8(1 H), 7.4 (2 H), 8.4 (3 H), 8.5 (3 H) and 8.8 ppm (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 114 Sodium D(-)-α-(3-acetyl-3-ethyl-ureido)-benzylpenicillin:

This penicillin was prepared from 18 parts by weight of ampicillin and 6parts by weight of N-acetyl-N-ethyl-carbamic acid chloride in the mannerdescribed in Example 113.

Yield: 62% β-Lactam content: 89%

    ______________________________________                                        Calculated:                                                                            C 50.6    H 5.4     N 11.2  S 6.5                                    Found:   C 50.7    H 6.3     N 10.8  S 6.9                                    ______________________________________                                    

NMR signals at 96 = 2.4-2.8 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.25(2 H), 7.7 (3 H), 8.45 (6 H) and 8.8 ppm (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 115 Sodium D(-)-α-(3-acetyl-3-n-propyl-ureido)-benzylpenicillin:

This penicillin was prepared from 28 parts by weight of ampicillin and10 parts by weight of N-acetyl-N-n-propylcarbamic acid chloride, in themanner described in Example 113.

Yield: 67% β-Lactam content: 89.

    ______________________________________                                        Calculated:                                                                            C 53.0    H 5.4     N 11.2  S 6.4                                    Found:   C 52.5    H(6.6)    N 10.5  S 6.4                                    ______________________________________                                    

NMR signals at τ =2.3-2.8 (5 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.3 (2H), 7.65 (3 H), 8.2-8.7 (8 H), and 9.1 ppm (3 H).

EXAMPLE 116 SodiumD(-)-α-(3-i-butyryl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 28 parts by weight of ampicillin and10 parts by weight of N-i-butyryl-N-methylcarbamic acid chloride, in themanner described in Example 113.

Yield: 33%. β-Lactam content: 91%.

    ______________________________________                                        Calculated:                                                                            C 51.1      H 5.6       N 10.8                                       Found:   C 50.8      H 6.4       N 10.9                                       ______________________________________                                    

NMR signals at τ = 2.4-2.8 (5 H), 4.45 (1 H), 4.55 (2 H), 5.85 (1 H),6.7 (3 H), 7.1 (1 H), 8.5 (6 H) and 8.9 ppm (6 H).

Effectiveness in animal experiments: B.

EXAMPLE 117 SodiumD(-)-α-(3-m-chlorobenzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 19.7 parts by weight of ampicillin and10 parts by weight of N-m-chlorobenzoyl-N-methyl-carbamic acid chloride,in the manner described in Example 113.

Yield: 62%. β-Lactam content: 86%.

    ______________________________________                                        Calculated:                                                                            C 51.5   H 4.4    Cl 6.1 N 9.6  S 5.6                                Found:   C 52.1   H(6.0)   Cl 5.6 N 9.4  S 5.5                                ______________________________________                                    

NMR signals at τ = 2.4-2.8 (9 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 6.85(3 H), and 8.45 ppm (6 H).

EXAMPLE 118 Sodiumα-(3-acetyl-3-methyl-ureido)-4-methylbenzylpenicillin:

This penicillin was prepared from 2.1 parts by weight ofα-amino-4-methyl-benzylpenicillin and 1.2 parts by weight ofN-acetyl-N-methyl-carbamic acid chloride, in the manner described inExample 113.

Yield: 45%. β-Lactam content: (determined by IR spectroscopy): 75%. NMRsignals at τ = 2.65 (2 H), 2.8 (2 H), 4.4-4.6 (3 H), 5.8 (1H), 6.75 (3H), 7.7 (6 H) and 8.25 to 8.55 ppm (6 H).

EXAMPLe 119 SodiumR,S-α-(3-dimethylaminocarbonyl-3-methyl-ureido)-4-methylbenzylpenicillin:

This penicillin was prepared from 1.8 parts by weight ofR,S-α-amino-4-methyl-benzylpenicillin and 1.6 parts by weight ofN-dimethylaminocarbonyl-N-methyl-carbamic acid chloride, as described inExample 83.

Yield: 39%. β-Lactam content: (determined by IR spectroscopy): 65% NMRsignals at τ = 2.5-2.9 (4 H), 4.4-4.7 (3 H), 5.8 (1 H), 6.9 (3 H), 7.05(6 H), 7.7 (3 H) and 8.4 ppm (6 H).

EXAMPLE 120 SodiumR,S-α-(3-dimethylaminocarbonyl-3-methyl-ureido)-4-chlorobenzylpenicillin:

This penicillin was prepared from 2.7 parts by weight ofR,S-α-amino-4-chloro-benzylpenicillin and 2.0 parts by weight ofN-dimethylaminocarbonyl-N-methyl-carbamic acid chloride, as described inExample 113.

Yield: 43%. β-Lactam content: (determined by IR spectroscopy): 55-60%.NMR signals at τ = 2.6 (4 H), 4.5 (3 H), 5.7 (1 H), 6.95 (3 H), 7.05 (6H) and 8.3 to 8.5 ppm (6 H).

EXAMPLe 121 SodiumR,S-α-(3-acetyl-3-methyl-ureido)-4-chlorobenzylpenicillin:

This penicillin was prepared from 1.8 parts by weight ofD,L-α-amino-4-chloro-benzylpenicillin and 1.0 part by weight ofN-acetyl-N-methyl-carbamic acid chloride, as described in Example 113.

Yield: 80%. β-Lactam content: (determined by IR spectroscopy): 55-60%.NMR signals at τ = 2.4-2.8 (4 H), 4.3-4.6 (3 H), 5.8 (1 H), 6.7 (3 H),7.65 (3 H) and 8.3-8.5 ppm (6 H).

EXAMPLE 122 SodiumD,L-α-(3-acetyl-3-methyl-ureido)-α-thienyl(2)-methylpenicillin

This penicillin was prepared from 3.5 parts by weight ofD,L-α-amino-α-thienyl(2)-methyl-penicillin and 1.7 parts by weight ofN-acetyl-N-methyl-carbamic acid chloride, as described in Example 113.

Yield: 42%. β-Lactam content: (determined by IR spectroscopy): 80%. NMRsignals at τ = 2.5-3.2 (3 H), 4.1-4.6 (3 H), 5.8 (1 H), 6.8 (3 H), 7.7(3 H) and 8.3-8.6 ppm (6 H).

EXAMPLE 123 SodiumD(-)-α-(3-[1-piperidyl]-carbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and13.5 parts by weight of N-(1-piperidylcarbonyl)N-methyl-carbamic acidchloride, in the manner described in EXAMPLE 59.

Yield (crude product): 66%. β-Lactam content: 97%.

    ______________________________________                                        Calculated:                                                                            C 53.4    H 5.6     N 12.9  S 5.9                                    Found:   C 53.1    H 6.5     N 12.3  S 6.3                                    ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.5 (3 H), 5.8 (1 H), 6.6 (4 H), 6.9 (3 H)and 8.4 ppm (12 H).

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Klebsiella K 10: 50 units/ml.

EXAMPLE 124 SodiumD(-)-α-(3-[1-pyrrolidyl]-carbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and12.6 parts by weight of N-(1-pyrrolidylcarbonyl)-M-methylcarbamic acidchloride, in the manner described in Example 59.

Yield (crude product): 72%. β-Lactam content: 96%.

    ______________________________________                                        Calculated:                                                                            N 13.3          S 6.1                                                Found:   N 13.2          S 6.1                                                ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.5 (3 H), 5.8 (1 H), 6.5-6.8 (4 H), 6.9(3 H), 8.0-8.3 (4 H) and 8.5 ppm (6 H).

Effectiveness against E. coli 14: 3.12 units/ml.

Effectiveness against Proteus 3400: 50 units/ml.

Effectiveness in animal experiments: A.

EXAMPLE 125 Sodium D(-)-α-(3-[4-morpholinyl]-carbonyl-3-methyl-ureido)benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and13.6 parts by weight of N-(4-morpholinylcarbonyl)-N-methyl-carbamic acidchloride, in the manner described in Example 59.

Yield (crude product): 80%. β-Lactam content: 93%.

    ______________________________________                                        Calculated:                                                                            N 12.9          S 5.9                                                Found:   N 11.8          S 5.9                                                ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.5 (3 H), 5.9 (1 H), 6.3-6.8 (8 H), 6.9(3 H) and 8.5 ppm (6 H).

Effectiveness against Proteus 1017: 50 units/ml.

Effectiveness in animal experiments: A.

EXAMPLE 126 SodiumD(-)-α-(3-diethylaminocarbonyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and12.7 parts by weight of N-diethylaminocarbonyl-N-methyl-carbamic acidchloride, in the manner described in Example 59.

Yield (crude product): 46%. β-Lactam content: 97%.

    ______________________________________                                        Calculated:                                                                            N 13.3          S 6.1                                                Found:   N 12.9          S 6.0                                                ______________________________________                                    

NMR signals at τ = 2.6 (5 H), 4.5 (3 H), 5.8 (1 H), 6.5-7.0 (7 H), 8.4(6 H) and 8.7-9.0 ppm (6 H).

Effectiveness against E. coli 14: 12.5 units/ml.

EXAMPLE 127 SodiumD(-)-α-(3-[2-nitro-4-chlorobenzoyl]-3-methyl-ureido)benzylpenicillin

This penicillin was prepared from 21 parts by weight of ampicillin and12.8 parts by weight of N-(2-nitro-4-chloro-benzoyl)-N-methyl-carbamicacid chloride, in the manner described in Example 59.

Yield (crude product): 81%. β-Lactam content: 95%.

    ______________________________________                                        Calculated:                                                                            N 11.4          S 5.2                                                Found:   N 10.6          S 5.1                                                ______________________________________                                    

NMR signals at τ = 1.7 (1 H), 2.1-2.5 (2 H), 2.6 (5 H), 4.3-4.6 (3 H),5.8 (1 H), 6.9 (3 H) and 8.4 ppm (6 H).

Effectiveness against Proteus 1017: 3.12 units/ml.

Effectiveness against Pseudomonas aerug. Bonn: 12.5 units/ml.

Effectiveness against Klebsiella K 10: 12.5 units/ml.

Effectiveness in animal experiments: A and B.

EXAMPLE 128 SodiumD(-)-α-(3-[2-bromobenzoyl]-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and18.3 parts by weight of N-(2-bromobenzoyl)-N-methyl-carbamic acidchloride, in the manner described in Example 59.

Yield (crude product): 64%. β-Lactam content: 95%. NMR signals at τ =2.2-2.7 (9 H), 4.3-4.6 (3 H), 5.8 (1 H), 7.0 (3 H) and 8.4 ppm (6 H).

Effectiveness against Proteus 1017: 1.56 units/ml.

Effectiveness against Pseudomonas aerug Bonn: 6.25 units/ml

Effectiveness in animal experiments: A and B.

EXAMPLE 129 SodiumD(-)-α-(3-[2-methylbenzoyl]-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 30 parts by weight of ampicillin and14.4 parts by weight of N-(2-methylbenzoyl)-N-methyl-carbamic acidchloride, in the manner described in Example 59.

Yield (crude product): 66%. β-Lactam content: 93%. NMR at τ = 2.4-2.8 (9H), 4.3-4.6 (3 H), 5.8 (1 H), 7.0 (3 H), 7.7 (3 H) and 8.5 ppm (6 H).

Effectiveness against Proteus 1017: 3.12 units/ml.

Effectiveness against Pseudomonas aerug. Bonn: 6.25 units/ml.

Effectiveness in animal experiments: A and B.

Example 130 Sodium D(-)-α-(3-acetyl-3-phenyl-ureido)-benzylpenicillin:

This penicillin was prepared from 10 parts by weight ofN-acetyl-N-phenylcarbamic acid chloride and 19 parts by weight ofampicillin, in the manner described in Example 113.

Yield: 86%. β-Lactam content: 85%.

    ______________________________________                                        Calculated:                                                                            C 53.1    H 5.0     N 9.9   S 5.7                                    Found:   C 53.6    H 5.5     N 9.8   S 5.7                                    ______________________________________                                    

NMR signals at τ = 2.4-2.8 (10 H), 4.4 (1 H), 4.55 (2 H), 5.8 (1 H), 8.1(3 H), 8.4 (3 H) and 8.5 ppm (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 131 SodiumD(-)-α-(3-m-nitrocinnamoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 18.9 parts by weight ofN-(m-nitrocinnamoyl)-N-methyl-carbamic acid chloride and 28 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 78%. β-Lactam content: 88%.

    ______________________________________                                        Calculated:                                                                            C 47.9    H 5.4     N 10.2  S 4.8                                    Found:   C 47.5    H 5.0     N 10.4  S 5.4                                    ______________________________________                                    

NMR signals at τ = 1.6 (1H), 1.7-2.9 (8 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1H), 6.6 (3 H) and 8.5 ppm (6 H).

Effectiveness in animal experiments: A and B

EXAMPLE 132 SodiumD(-)-α-(3-[4-nitrophenacetyl]-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 16.3 parts by weight ofN-p-nitrophenacetyl-N-methyl-carbamic acid chloride and 28 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 92%. β-Lactam content: 84%.

    ______________________________________                                        Calculated:                                                                            C 51.1    H 4.6     N 11.5  S 5.3                                    Found:   C 51.3    H 5.4     N 11.2  S 5.7                                    ______________________________________                                    

NMR signals at τ = 1.8 (2 H), 2.5 (2 H), 2.6 (5 H), 4.4 (1 H), 4.55 (2H), 5.8 (1 H), 5.85 (2 H), 6.7 (3 H), 8.4 (3 H), and 8.5 ppm (3 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 133 D(-)-α-(1-Imidazolidin-2-on-1-ylcarbonylamino)-benzylpenicillin:

This penicillin was prepared from 5.4 parts by weight ofN-chlorocarbonyl-imidazolidin-2-one and 12.7 parts by weight ofampicillin in the manner described in Example 59. After acidification,the product was obtained as the free penicillin acid, which is sparinglysoluble in ethyl acetate, and which was filtered off, washed with waterand dried over P₂ O₅ in vacuo.

Yield: 72%. β-Lactam content: 93%.

    ______________________________________                                        Calculated:                                                                            C 50.1    H 5.0     N 14.6  S 6.7                                    Found:   C 50.1    H 5.6     N 13.8  S 6.8                                    ______________________________________                                    

NMR signals at τ = 0.9 (2 H), 2.35 (1 H), 2.6 (5 H), 4.25 (1 H), 4.55 (2H), 5.7 (1 H), 6.0-7.0 (4 H), 8.4 (3 H) and 8.55 ppm (3 H)

Solvent: DMSO-D₆.

EXAMPLE 134

Sodium D(-)-α-(1-piperidin-2-on-1-yl-carbonylamino)-benzylpenicillin:

This penicillin was prepared from 9 parts by weight of1-chlorocarbonyl-2-chloro-1,4,5,6-tetrahydropyridine and 21 parts byweight of ampicillin in the manner described in Example 113.

Yield: 85%. β-Lactam content: 89%.

NMR signals at τ = 2.4-2.8 (5 H), 4.4 (1 H), 4.45 (1 H), 4.55 (1 H), 5.8(1 H), 6.15-6.5 (2 H), 7.6-8.0 (2 H) and 8.0-8.6 ppm (10 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 135 Sodiumα-(3-o-chlorobenzoyl-3-methyl-ureido)-α-thienyl(2)methylpenicillin:

This penicillin was prepared from 1.9 parts by weight ofN-o-chlorobenzoyl-N-methylcarbamic acid chloride and 1.5 parts by weightof α-amino-α-thienyl(2)-methylpenicillin in the manner described inExample 113.

Yield: 35%. β-Lactam content: 55-60% (estimated from the IR spectrum).

NMR signals at τ = 2.4-3.1 (7 H), 4.3-4.5 (3 H), 5.8 (1 H), 6.9 (3 H)and 8.2-8.6 ppm (6 H).

Effectiveness in animal experiments: B.

EXAMPLE 136 SodiumD(-)-α-(3-methyl-1,3-diazacyclohexan-2-on-1-yl-carbonyl-amino)-benzylpenicillin:

This penicillin was prepared from 12.4 parts by weight of1-chloro-carbonyl-2-oxo-3-methyl-1,3-diazacyclohexane and 17.5 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 46%. β-Lactam content: 90%.

    ______________________________________                                        Calculated:                                                                            C 50.1    H 5.3     N 13.3  S 6.1                                    Found:   C 50.4    H 6.2     N 13.1  S 6.4                                    ______________________________________                                    

NMR signals at τ = 2.3-2.8 (5 H), 4.3-4.6 (3 H), 5.8 (1 H), 6.25 (2 H),6.4-6.8 (2 H), 7.0 (3 H), 8.0 (2 H), 8.4 (3 H) and 8.5 ppm (3 H).

EXAMPLE 137 SodiumD(-)-α-(3-o-fluorobenzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 9.05 parts by weight ofN-o-fluorobenzoyl-N-methyl-carbamic acid chloride and 17.5 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 88%. β-Lactam content: 92%.

    ______________________________________                                        Calculated:                                                                            C 54.6    H 4.4     N 10.2  S 5.8                                    Found:   C 54.2    H(5.6)    N 10.1  S 5.8                                    ______________________________________                                    

NMR signals at τ = 2.4-2.9 (9 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 6.8(3 H) and 8.5 ppm (6 H).

EXAMPLE 138 SodiumD(-)-α-(3-o-chlorobenzoyl-3-ethyl-ureido)-benzylpenicillin:

This penicillin was prepared from 10.7 parts by weight ofN-o-chlorobenzoyl-N-ethyl-carbamic acid chloride and 17.5 parts byweight of ampicillin, in the manner described in Example 113

Yield: 90% β-Lactam content: 93%

    ______________________________________                                        Calculated:                                                                            C 52.5   H 4.6    Cl 6.0 N 9.4  S 5.4                                Found:   C 52.3   H 5.4    Cl 5.6 N 9.2  S 5.4                                ______________________________________                                    

NMR signals at τ = 2.3-2.8 (9 H), 4.35 (1 H), 4.5 (2 H), 5.8 (1 H), 6.4(2 H), 8.4 (3 H), 8.5 (3 H) and 9.0 ppm (3 H).

EXAMPLE 139 SodiumD(-)-α-(3-o-chlorobenzoyl-3-n-propyl-ureido)-benzylpenicillin:

This penicillin was prepared from 11.0 parts by weight ofN-o-chlorobenzoyl-N-n-propyl-carbamic acid chloride and 17.5 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 82% β-Lactam content: 92%

    ______________________________________                                        Calculated:                                                                            C 53.3   Cl 5.8   N 9.2  H 4.8  S 5.3                                Found:   C 53.7   Cl 5.4   N 9.2  H(6.2) S 5.6                                ______________________________________                                    

NMR signals τ = 2.3-2.8 (9 H), 4.4 (1 H), 4.5 (2 H), 5.8 (1 H), 6.3-6.7(2 H), 8.2-8.7 (2 H), 8.4 (3 H), 8.5 (3 H) and 9.3 ppm (3 H).

EXAMPLE 140 SodiumD(-)-α-(3-o-nitrobenzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 12.1 parts by weight ofN-o-nitrobenzoyl-N-methyl-carbamic acid chloride and 21 parts by weightof ampicillin, in the manner described in Example 113.

Yield: 94% β-Lactam content: 92%

    ______________________________________                                        Calculated:                                                                            C 51.1    H 4.3     N 11.9  S 5.5                                    Found:   C 50.9    H 5.3     N 11.1  S 5.6                                    ______________________________________                                    

NMR signals at τ = 1.75 (1 H), 2.05-2.8 (8 H), 4.35 (1 H), 4.5 (2 H),5.8 (1 H), 6.95 (3 H), 8.4 (3 H) and 8.5 (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 141 SodiumD(-)-α-(3,o,o'-dichlorobenzoyl-3-methyl-ureido)-benzylpenicillin:

This penicillin was prepared from 13.3 parts by weight ofN-o,o'-dichlorobenzoyl-N-methyl-carbamic acid chloride and 21 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 91% β-Lactam content: 91%

    ______________________________________                                        Calculated:                                                                            C 48.6   H 4.0    Cl 11.5                                                                              N 9.1  S 5.2                                Found:   C 48.9   H 4.5    Cl 11.1                                                                              N 8.9  S 5.3                                ______________________________________                                    

NMR signals at τ = 2.3-2.8 (8 H), 4.3 (1 H), 4.5 (2 H), 5.75 (1 H), 6.9(3 H), 8.4 (3 H) and 8.5 ppm (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 142 SodiumD(-)-α-(3-[2,4-dichlorobenzoyl]-3-methyl-ureido)benzylpenicillin:

This penicillin was prepared from 13.3 parts by weight ofN-(2,4-dichlorobenzoyl)-N-methyl-carbamic acid chloride and 21 parts byweight of ampicillin, in the manner described in Example 113.

Yield: 84%. β-Lactam content: 92%.

    ______________________________________                                        Calculated:                                                                            C 48.6   H 4.0    Cl 11.5                                                                              N 9.1  S 5.2                                Found:   C 48.7   H 4.6    Cl 10.9                                                                              N 9.0  S 5.8                                ______________________________________                                    

NMR signals at τ = 2.4 (1 H), 2.4-2.8 (7 H), 4.35 (1 H), 4.5 (2 H), 5.8(1 H), 6.9 (3 H), 8.4 (3 H) and 8.5 ppm (3 H).

Effectiveness in animal experiments: A and B.

EXAMPLE 143 SodiumD(-)-α-(3-propionyl-3-phenyl-ureido)-benzylpenicillin:

This penicillin was prepared from 15.5 parts by weight ofN-propionyl-N-phenyl-carbamic acid chloride and 27.5 parts by weight ofampicillin, in the manner described in Example 113.

Yield: 78% β-Lactam content: 87%

    ______________________________________                                        Calculated:                                                                            C 55.3    H 5.1     N 9.9   S 5.7                                    Found:   C 55.1    H 5.1     N 9.8   S 6.0                                    ______________________________________                                    

NMR signals at τ = 2.2-3.0 (10 H), 4.4 (1 H), 4.5 (2 H), 5.75 (1 H), 7.9(2 H), 8.4 (3 H), 8.5 (3 H) and 9.0 ppm (3 H).

Effectiveness in animal experiments: B.

EXAMPLE 144 A.D(-)-α-(Imidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin:

14 parts by weight of D-α-aminobenzylpenicillin (ampicillin) weresuspended in 80% strength aqueous tetrahydrofurane (130 parts by volume)and sufficient triethylamine (approx. 6.5 parts by volume) was addeddropwise, while stirring, at 20°C, that a clear solution was justproduced and the pH value was between 7.5 and 8.2 (glass electrode). Themixture was now cooled to 0°C and a solution of 5.4 parts by weight ofN-chlorocarbonyl-imidazolidin-2-one in 25 parts by volume of absolutetetrahydrofurane was added dropwise over the course of 30 minutes, whilecooling with ice and stirring vigorously, the pH value being keptbetween 7.5 and 8.0 by simultaneous addition of triethylamine. Themixture was further stirred for 30 minutes at 0°C and subsequently atroom temperature until no further addition of triethylamine wasnecessary to maintain the pH value of 7.5. 130 parts by volume of waterwere now added and the tetrahydrofurane was largely removed in a rotaryevaporator at room temperature. The aqueous solution which remained wasonce extracted by shaking with ether, covered with 300 parts by volumeof ethyl acetate, cooled to 0°C and treated with sufficient dilutehydrochloric acid, while stirring and cooling with ice, to establish apH value of 1.5 to 2.0. The organic phase was separated off, the aqueoussuspension was again extracted with about 300 parts by volume of ethylacetate, and the organic extracts were combined.

The penicillin, which is rather sparingly soluble in ethyl acetate andwhich was suspended in the aqueous phase, was filtered off, carefullywashed with ice water until free of acid, and dried in vacuo at about 1mm Hg over P₂ O₅. The substance is crystalline; long needles are visibleunder the microscope.

Yield: 71%. β-Lactam content: 93%.

    ______________________________________                                        Calculated:                                                                            C 50.1    H 5.0     N 14.6  S 6.7                                    Found:   C 50.1    H 5.6     N 13.8  S 6.8                                    ______________________________________                                    

NMR signals (dimethylsulphoxide-d₆ as the solvent) at τ = 0.9 (2 H),2.35 (1 H), 2.6 (5 H), 4.25 (1 H), 4.55 (2 H), 5.7 (1 H), 6.0-7.0 (4 H),8.4 (3 H) and 8.55 ppm (3 H). IR bands at 3380, 3230, 1784, 1728, 1687,1639, 1520, 1375, 1219 and 735 cm.sup.⁻¹ .

According to separation in a paper chromatogram and subsequentdevelopment with B. subtilis, the product only contains oneantibiotically active component.

A further 0.45 part by weight (2.6% of theory) of the penicillin, in theform of its sodium salt, could be isolated from the ethyl acetateextract after addition of about 2 parts by volume of a 1 molar solutionof sodium 2-ethyl-hexanoate in ether containing methanol.

The free acid of the penicillin can be easily converted into thechemotherapeutically usable salts by conventional processes. (SeeExample 150A).

B. 1-Chlorocarbonyl-imidazolidione(2).

4 parts by weight of phosgene in 10 parts by volume of absolutetetrahydrofurane were added dropwise, over the course of 15 minutes, toa vigorously stirred solution of 3.5 parts by weight of imidazolidone(2) [manufactured according to Fischer and Koch, Ann, 232, page 224(1886)] in 50 parts by volume of absolute tetrahydrofurane. Thereafterthe reaction mixture was stirred from 3 hours at 10°C and a stream ofdry air was then passed through it, in order to blow out thehydrochloric acid formed, and remnants of phosgene. The mixture was nowevaporated to dryness on a rotary evaporator in vacuo, and the solidresidue was dried over concentrated sulphuric acid and at about 12 mmHg.

Yield: 93%. Melting point = 150°C after recrystallisation fromacetone-pentane.

    ______________________________________                                        Calculated:                                                                            C 32.3    H 3.4     N 18.8  Cl 23.9                                  Found:   C 32.3    H(4.5)    N 18.7  Cl 23.9                                  ______________________________________                                    

NMR signals at τ = 5.7 to 6.1 (2 H) and 6.3 to 6.7 (2 H), (acetone-d₆ asthe solvent), symmetrical A₂ B₂ -system. IR bands at 3230, 1790, 1700,1270 and 1150 cm.sup.⁻¹.

EXAMPLE 145

If, in the procedure of Example 144, the D-α-aminobenzylpenicillin usedtherein is replaced by:

0.04 mol of α-amino-p-methylbenzylpenicillin,

α-amino-p-chlorobenzylpenicillin,

α-amino-p-methylthiobenzylpenicillin,

α-amino-α-(2)thienylmethylpenicillin or

α-amino-α-(3)thienylmethylpenicillin,

the following penicillins are obtained:

α-(imidazolidin-2-on-1-yl-carbonylamino)-p-methylbenzylpenicillin,

α-(imidazolidin-2-on-1-yl-carbonylamino)-p-chlorobenzylpenicillin,

α-(imidazolidin-2-on-1-yl-carbonylamino)-p-methylthiobenzylpenicillin

α-(imidazolidin-2-on-1-yl-carbonylamino)-α-(2)-thienylmethylpenicillinor

α-(imidazolidin-2-on-1-yl-carbonylamino)-α-(3)thienylmethylpenicillin.

EXAMPLE 146

If, in the procedure of Example 144, the 1-chlorocarbonylimidazolidoneused therein is replaced by 0.035 mol of:

1-chlorocarbonyl-1,3-diazacyclohexan-2-one,

1-chlorocarbonyl-1,3-diazacycloheptan-2-one,

1-chlorocarbonyl-5-methyl-imidazolidone(2),

1-chlorocarbonyl-4-methyl-imidazolidone(2),

1-chlorocarbonyl-5,5-dimethyl-imidazolidone(2),

1-chlorocarbonyl-4,4-dimethyl-imidazolidone(2),

1-chlorocarbonyl-4,5-cis-dimethyl-imidazolidone(2),

1-chlorocarbonyl-4,5-trans-dimethyl-imidazolidone,

1-chlorocarbonyl-benzimidazolone,

1-chlorocarbonyl-6-methyl-benzimidazolone,

1-chlorocarbonyl-5-methyl-benzimidazolone,

1-chlorocarbonyl-4-methyl-benzimidazolone,

1-chlorocarbonyl-7-methylbenzimidazolone,

1-chlorocarbonyl-5-nitrobenzimidazolone,

1-chlorocarbonyl-6-nitrobenzimidazolone,

1-chlorocarbonyl-hexahydrobenzimidazolone(2),

1-chlorocarbonyl-6-aza-benzimidazolone,

1-chlorocarbonyl-5-aza-benzimidazolone,

1-chlorocarbonyl-5-carbethoxy-benzimidazolone,

1-chlorocarbonyl-6-carbethoxy-benzimidazolone or2-chlorocarbonyl-2,4-diazabicyclo[3,2,2]-nonan-3-one,

the following penicillins are obtained:

D(-)-α-(1,3-diazacyclohexan-2-on-1-yl-carbonylamino)-benzylpenicillin

D(-)-α-(1,3-diazacycloheptan-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(5-methyl-imidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4-methylimidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(5,5-dimethylimidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4,4-dimethylimidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4,5-cis-dimethylimidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4,5-trans-dimethylimidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(benzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(6-methylbenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(5-methylbenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4-methylbenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(7-methylbenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(5-nitrobenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(6-nitrobenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(hexahydrobenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(6-azabenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin

D(-)-α-(5-azabenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin

D(-)-α-(5-carbethoxybenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(6-carbethoxybenzimidazolin-2-on-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(2,4-diazabicyclo[3,2,2]nonan-3-on-2-yl-carbonylamino)-benzylpenicillin.

EXAMPLE 147 A. SodiumD(-)-α-(imidazolidine-2-thion-1-yl-carbonylaminobenzylpenicillin:

8.5 parts by weight of 1-chlorocarbonyl-imidazolidine 2-thione werereacted with 17.5 parts by weight of D(-)-α-aminobenzylpenicillin in 170parts by volume of 80% strength aqueous tetrahydrofurane, at 0°C and pH7.5 to 8.0 (glass electrode), whilst stirring. Triethylamine were addedgradually to maintain the pH value. The mixture was further stirred atroom temperature until no further addition of triethylamine wasnecessary to maintain the pH at 7.5. Thereafter, 150 parts by volume ofwater were added, a pH of 6.5 was established by means of a littledilute hydrochloric acid, and the tetrahydrofurane was stripped off in arotary evaporator at room temperature. The mixture was now extractedonce with ether, the aqueous phase was covered with 300 parts by volumeof ethyl acetate, the whole was cooled at 0°C, and dilute hydrochloricacid was introduced, while stirring and cooling with ice, until a pHvalue of 1.5 to 2.0 was reached. The organic phase was separated off,the aqueous solution was again extracted with 300 parts by volume ofethyl acetate, and the organic solutions were combined and subsequentlydried with MgSO₄. On adding about 40 parts by volume of a 1 molarsolution of sodium 2-ethylhexanoate in ether containing methanol, thesodium salt of the penicillin precipitated. The bulk of the ethylacetate was stripped from the suspension in vacuo, and the residue wasdissolved in methanol and added dropwise to a mixture of 300 parts byvolume of ether and 30 parts by volume of methanol. The ether/methanolmixture was decanted from the precipitated product after it had stoodfor a short time, and the product was again repeatedly worked withether, filtered off and dried over P₂ O₅ in a vacuum desiccator.

Effectiveness against Psdm. aerug. Bonn: 25 units/ml.

Effectiveness against Proteus 3400: 50 units/ml.

Yield: 40% β-Lactam content: 90% (estimated on the basis of the β-lactamband of the IR spectrum). NMR signals (methanol-d₄ as the solvent) at τ= 2.3 to 2.8 (5 H), 4.4 (1 H), 4.55 (2 H), 5.85 (1 H), 6.0 to 6.5 (4 H),8.4 (3 H) and 8.5 ppm (3 H). IR bands at 3320, 1760, 1720, 1665, 1602,1520, 1365, and 1255 cm.sup.⁻¹.

B. 1-Trimethylsilyl-imidazolidine-2-thione:

30.6 parts by weight of imidazolidine-2-thione were boiled overnightwith 54.4 parts by weight of trimethylchlorosilane and 51.5 parts byweight of triethylamine in absolute tetrahydrofurane. The warmsuspension was freed of the precipitated triethylamine hydrochloride byfiltration, and the filtrate was evaporated and dried in a vacuumdesiccator.

Melting point: approx. 130°C. Yield: 97%.

    ______________________________________                                        Calculated:                                                                            N 14.4          S 16.5                                               Found:   N 13.8          S 16.9                                               ______________________________________                                    

Strong Si-C stretching vibration in the IR spectrum at 850 cm.sup.⁻¹.

C. 1-Chlorocarbonyl-imidazolidine-2-thione:

50 parts by weight of 1-trimethylsilyl-imidazolidine-2-thione in 150parts by volume of methylene chloride were treated with 35 parts byweight of phosgene in 50 parts by volume of methylene chloride over thecourse of 2 hours at 0°C. The mixture was stirred for 24 hours at 0°C,the methylene chloride was subsequently stripped off, and the residuewas dried in a high vacuum. Semi-solid mass, incompletely soluble inacetone.

Crude yield: 97%. IR bands at 1830, 1590 and 1240 cm.sup.⁻¹.

EXAMPLE 148

If, following the procedures desired in Example 147A 17.5 parts byweight of ampicillin are reacted with 0.05 mol of:

1-chlorocarbonyl-1,3-diazacyclohexane-2-thione,

1-chlorocarbonyl-4-methylimidazolidine-2-thione,

1-chlorocarbonyl-5-methylimidazolidine-2-thione,

1-chlorocarbonyl-4,4-dimethylimidazolidine-2-thione,

1-chlorocarbonyl-5,5-dimethylimidazolidine-2-thione or

1-chlorocarbonyl-4,5-dimethylimidazolidine-2-thione,

the following penicillins are obtained in the form of their sodiumsalts:

D(-)-α-(1,3-diazacyclohexane-2-thion-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4-methylimidazolidine-2-thion-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(5-methylimidazolidine-2-thion-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(4,4-dimethylimidazolidine-2-thion-1-yl-carbonylamino)-benzylpenicillin,

D(-)-α-(5,5-dimethylimidazolidine-2-thion-1-yl-carbonylamino)-benzylpenicillinor

D(-)-α-(4,5-dimethylimidazolidine-2-thion-1-yl-carbonylamino)-benzylpenicillin.

EXAMPLE 149

If, in the procedure of Example 147-A the D-α-aminobenzylpenicillin usedthere is replaced by 0.05 mol of

α-amino-p-methylbenzylpenicillin,

α-amono-p-chlorobenzylpenicillin,

α-amino-p-methylthiobenzylpenicillin,

α-amino-α-(2)-thienylmethylpenicillin or

α-amino-α-(3)-thienylmethylpenicillin,

the following penicillins are obtained in the form of their sodiumsalts:

α-(imidazolidine-2-thion-1-yl-carbonylamino)-p-methylbenzylpenicillin

α-(imidazolidine-2-thion-1-yl-carbonylamino)-p-chlorobenzylpenicillin

α-(imidazolidine-2-thion-1-yl-carbonylamino)-p-methylthiobenzylpenicillin,

α-(imidazolidine-2-thion-1-yl-carbonylamino)-α-(2)thienylmethylpenicillinor

α-(imidazolidine-2-thion-1-yl-carbonylamino)-α-(3)thienylmethylpenicillin.

EXAMPLE 150 A. SodiumD(-)-α-(imidazolidin-2-on-1-yl-carbonylamino)benzylpenicillin:

5.5 parts by weight ofD(-)-α-(imidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillin, whichwas obtained, moist with water, according to the instructions of Example144, were dissolved in 13 parts by volume of dimethylacetamide whilecooling with ice, and subsequently treated with 10 parts by volume of a1 molar solution of sodium 2-ethylhexanoate in ether containingmethanol. The resulting clear solution was added dropwise over thecourse of a few minutes to a mixture, cooled to -20°C, of 200 parts byvolume of ether and 20 parts by volume of methanol, whereupon the sodiumsalt of the penicillin separated out as a finely granular precipitate,which was filtered off and thoroughly washed with anhydrous ether.

Yield: 81% relative to 1-chlorocarbonyl-imidazolidin-2-one employed.β-Lactam content: 90% (determined on the basis of the intensity of theβ-lactam carbonyl band of the IR spectrum). IR bands at 3290, 1770,1715, 1647, 1538 and 1276 cm.sup.⁻¹. (IR spectrum in Nujol).

B. Crystalline sodiumD(-)-α-(imidazolidin-2-on-1-yl-carbonyl-amino)-benzylpenicillin:

0.4 part by weight of the product from Example 92A was dissolved in 0.5part by volume of water to give a clear solution. 1.3 parts by volume ofethanol were added and the mixture slowly diluted with 3.0 parts byvolume of ethyl acetate, while shaking. 0.2 part by weight of sodiumD(-)-α-(imidazolidin-2-on-1-yl-carbonylamino)-benzylpenicillincrystallised overnight from the initially clear solution, in the form ofbundles of fine needles.

Decomposition range: 200° - 220°C. IR bands at 3370, 3325, 1775, 1728,1688, 1640 and 1275 cm.sup.⁻¹.

FIGS. 3, 4 and 5 show, for comparison purposes, the IR spectra ofD(-)-α-(imidazolidin-2-on-1-yl-carbonylamino)benzylpenicillin as thefree acid and as the amorphous and crystalline sodium salt.

What is claimed is:
 1. A compound selected from the group consisting ofa penicillin of the formula: ##EQU21## and the pharmaceuticallyacceptable nontoxic salts thereof whereinthe carbon atom designated by *constitutes a center of chirality, ##EQU22## in which m is 3, and B is##SPC4##wherein R₄, r₅ and R₆ are the same or different, and are eachhydrogen, halo, lower alkyl, lower alkoxy, lower alkylthio, loweralkylthionyl, lower alkylsulphonyl, nitro, di(lower alkyl)amino, loweralkanoylamino, hydroxy, or lower alkanoyloxy.
 2. A compound according toclaim 1 wherein B is phenyl.
 3. A penicillin according to claim 1 in theform of the sodium salt.
 4. The compound according to claim 2 which isα-(pyrrolid-2-on-1-yl-carbonylamino)-α-p-tolyl-methylpenicillin or thesodium salt thereof.
 5. The compound according to claim 2 which isD(-)-α-(pyrrolid-2-on-1-yl-carbonylamino)-benzylpenicillin or the sodiumsalt thereof.